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. Author manuscript; available in PMC: 2025 Mar 1.
Published in final edited form as: Clin Lung Cancer. 2023 Dec 12;25(2):159–167. doi: 10.1016/j.cllc.2023.12.002

HIV Associated Lung Cancer: Unique Clinicopathologic Features and Immune Biomarkers Impacting Lung Cancer Screening and Management

Ayse Ece Cali Daylan 1,#, Catarina Martins Maia 2,#, Shirin Attarian 1,‡, Xiaoling Guo 3, Mindy Ginsberg 4, Enrico Castellucci 1, Rasim Gucalp 1, Missak Haigentz 1,†, Balazs Halmos 1, Haiying Cheng 1
PMCID: PMC10922688  NIHMSID: NIHMS1955222  PMID: 38158315

Abstract

HIV associated lung cancer often manifests at a young age with an advanced stage, and the rate of lung cancer diagnosis by screening program remains low. The majority of HIV associated lung cancer exhibit limited PD-L1 expression, although high CD8+ cells are observed in high PD-L1 tumors. Despite these challenges, immunotherapy is well-tolerated with reasonable disease control.

Objectives:

Lung cancer contributes significantly to morbidity and mortality in people with HIV (PWH). We study the clinicopathologic characteristics and immune microenvironment in HIV associated lung cancer.

Material and Methods:

Clinicopathological characteristics including immunotherapy outcomes were collected for 174 PWH diagnosed with lung cancer. Immunohistochemical staining for PD-L1, CD4, and CD8 was performed.

Results:

At diagnosis, patients with HIV associated lung cancer were significantly younger (56.9 vs. 69 years, P < .0001) and more frequently had advanced disease (70% vs. 53%, P = .01). The majority were African American (60% vs. 42%, P < .0001) and were smoking at the time of diagnosis or smoked in the past (98% vs. 86%, P = .0001). Only 10% of HIV associated lung cancer was diagnosed through the screening program. The median CD4+ lymphocyte count was 334 cells/μL, 31% had a CD4 ≤200 cells/μL and 63% of the cohort was virally suppressed. HIV associated non–small-cell lung cancer(NSCLC) was characterized by limited PD-L1 expression compared to the HIV negative cohort, 64% vs. 31% had TPS <1%, and 20% vs. 34% had TPS≥50%, respectively (P = .04). Higher CD8+ TILs were detected in PD-L1-high tumors (P < .0001). 50% of patients achieved disease control in the metastatic setting with the use of immunotherapy, and there were no new safety signals in 19 PWH treated with immunotherapy.

Conclusion:

Lung cancer in PWH demonstrates unique features highlighting the need for a specialized screening program. Despite low PD-L1 expression, immunotherapy is well tolerated with reasonable disease control. Altered immune system in lung cancer pathogenesis in PWH should be further investigated.

Keywords: Immunotherapy, PD-L1, People living with HIV, PWH, Tumor infiltrating lymphocytes

Introduction

Since the implementation of the use of combination antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) in 1996, there has been a notable reduction in HIV-associated morbidity and mortality, including a decline in the incidence of certain cancers like Kaposi sarcoma, Non-Hodgkin lymphomas. However, the incidence of several other types of cancer, like lung, anal, liver cancer has increased as the population living with HIV has been aging.1-6 In the new ART era, lung cancer has emerged as a significant cause of morbidity and mortality in PWH.7-9

Prior retrospective cohort analyses have described 2-to-4 fold increased risk of lung cancer among PWH compared to the general population, which is partly due to higher smoking rates, but HIV might also act as an independent risk factor.3,10-12 Pulmonary infections like tuberculosis may also contribute to the increased lung cancer risk in this population.13 The clinical characteristics of lung cancer in PWH differ from the general lung cancer population. It tends to present at a younger age.14-16 In addition, it poses a substantial health risk as the lung cancer in this group is estimated to account for up to 40% of all cancer mortality and up to 10% of deaths not directly related to HIV in PWH.17-19 The worse survival in PWH diagnosed with lung cancer compared to lung cancer patients without concomitant HIV infection has been demonstrated in several studies.20-22 A recent retrospective study evaluating lung cancer in PWH demonstrated that despite having a similar histology, stage, and treatment regimens, PWH group had poorer clinical outcomes with a median overall survival 10 months shorter in this cohort (12.4 vs. 22.8 months).14

A recent large population-based registry study investigated lung cancer incidence in PWH. This study revealed that despite a reduction in lung cancer incidence rate in PWH between 2001 and 2016, the lung cancer risk in PWH remains elevated with an incidence ratio of 1.48 compared to the general population.23 This study also revealed that lung cancer is rising as one of the main cancers affecting PWH, especially in the older group. The cumulative incidence of lung cancer in PWH aged 50 or older was equivalent to non-Hodgkin lymphoma, and higher than Kaposi sarcoma.2 These findings reinforce the rise of lung cancer as a significant health concern in PWH.

Recent advances in the general management of lung cancer, including the introduction of lung cancer screening, improved diagnostic tools, and novel treatment modalities, including immunotherapy and targeted therapies, have led to significant survival benefits for both localized and metastatic lung cancer. Untreated HIV infection decreases CD4+ T cell counts, perturbs T cell receptor diversity, and affects T cell mediated immunity. HIV treatment with ART reverses most of these perturbations, but immune recovery may not be complete. These immune changes lead to decreased immunosurveillance and increased risk of cancers.24 Furthermore, they may also affect the efficacy and safety of immunotherapy in PWH. Even though PWH were historically excluded from most oncology clinical trials, recently, 2 prospective studies and multiple retrospective analyses have addressed the safety and efficacy of immunotherapy in this population. A recent phase I study evaluating the safety of PD-(L)1 inhibitors in PWH on ART with CD4+ T-cell counts of more than 100 cells/μL was encouraging, mainly revealing grade 1 and grade 2 immunotherapy related adverse effects.25 Another prospective study of durvalumab in 20 PWH did not reveal any new safety signals. HIV viral load, peripheral CD4 and CD8 counts have remained stable throughout immunotherapy. This cohort was mostly comprised of NSCLC.26 Multiple retrospective studies showed that the safety and efficacy of immunotherapy was similar in PWH compared to the matched cohort without HIV regardless of peripheral CD4 count.27,28 A systematic review of PWH treated with immunotherapy also showed no new safety signals with anti-tumor activity in various cancers.29 These studies demonstrate recent efforts to better characterize the outcomes of novel treatment approaches for HIV associated lung cancer. It is critical to better understand this unique population’s clinical characteristics, including the immunotherapy response and tumor immune microenvironment. This study aims to characterize the specific clinicopathologic characteristics of PWH diagnosed with lung cancer, including PD-L1 expression, tumor-infiltrating lymphocytes, and immunotherapy response.

Material and Methods

Montefiore Health System provides medical care to one of the largest populations of PWH in the United States. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Montefiore Medical Center/Albert Einstein College of Medicine. Patient consent was waived due to the retrospective, observational nature of the study. We reviewed medical record databases and identified 201 PWH who were diagnosed with lung cancer between 2000 and 2020. Of these patients, 27 were excluded (Figure 1) due to the lack of histological confirmation of lung cancer, lack of confirmed HIV infection status, or the presence of a concomitant second primary cancer diagnosis. Among the remaining 174 patients, available demographic and clinicopathologic data were collected, including age at diagnosis, sex, ethnicity, smoking status, stage at diagnosis, and histology. HIV characteristics including the CD4+ and CD8+ lymphocyte count, HIV viral load at the time of lung cancer diagnosis were collected. We compared HIV associated lung cancer (n = 174) diagnosed between 2000 and 2020 with lung cancer patients without HIV diagnosis (n = 991) diagnosed during 2012 to 2016 regarding 6 variables: age, ethnicity, sex, smoking status, stage of disease at diagnosis, and histology.

Figure 1.

Figure 1

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CONSORT diagram.

In order to pursue immune biomarker analyses, we identified 56 PWH with lung cancer with sufficient tissue to evaluate the expression of the programmed death ligand 1 (PD-L1). To assess PD-L1 Tumor Proportion Score (TPS), the FDA-approved 22C3 (monoclonal mouse anti-PD-L1, clone 22C3) pharmDx qualitative immunohistochemical assay was used with the EnVision FLEX visualization system on Dako Automated Link 48. In addition to PD-L1 TPS assessment, where sufficient tissue was available, further IHC studies were performed to evaluate tumor infiltrating lymphocytes (25 NSCLC, 3 SCLC). The specific immunohistochemical stain antibodies used were CD4 (1:25, Thermo Fisher Scientific 4B12) and CD8 (1:200, C8/144B) to determine CD4 and CD8-positive tumor-infiltrating lymphocytes. Formalin-fixed paraffin-embedded tissue sections were used for immunohistochemical stains performed on an automated immunostainer (Dako, Carpinteria, CA). Antigen retrieval was performed with either a citrate buffer (pH 6.1), EDTA buffer (pH 9), or Trilogy. For immunohistochemistry (IHC) analyses, the Dako EnVision+ system was used with the horseradish peroxidase 2-step immunohistochemical staining technique.

We further evaluated 19 patients with HIV associated lung cancer who received immunotherapy and had a documented response to allow assessment of treatment benefit. Immune mediated adverse events were assessed by the treating clinicians and recorded during routine care in patients’ electronic medical record and severity was graded per Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Statistical Analysis

We compared demographic and clinical characteristics between the 2 groups of lung cancer patients, PWH and patients without an HIV diagnosis. We used the chi-square test for all variables except for age, where a 2-tail, 2-sample unequal variance (heteroscedastic) t test was used. We used ANOVA testing to compare CD4 and CD8 cell counts between different PD-L1 groups. We calculated Pearson correlation coefficient to compare intratumoral CD4 and CD8 counts with peripheral CD4 and CD8 counts. We used t-test to compare intratumoral CD4 and CD8 counts between groups with peripheral CD4 count > 200 cells/μL and CD4 count ≤ 200 cells/μL and HIV viral load <200 copies/mL and ≥ 200 copies/mL.

Results

Baseline Demographic and Clinicopathologic Characteristics of Patients With HIV Associated Lung Cancer in Comparison to Lung Cancer Patients Without an HIV Diagnosis

A total of 174 patients were identified as having confirmed HIV infection (PWH) and primary lung cancer diagnosed during the study interval (2000-2020). Their baseline demographic and clinicopathological characteristics are shown in Table 1 in comparison to the lung cancer patients without HIV diagnosis (N = 991), diagnosed between 2012 and 2016 . In our study, HIV associated lung cancer were diagnosed younger with a median age at diagnosis of 56.9 years vs. 69 years (P < .0001). The gender distribution was predominantly male patients composing 60% in HIV positive cohort and 51% in HIV negative cohort, (P = .02). HIV associated lung cancer was more commonly seen in African American population 60% vs. 42% (P < .0001). The incidence was similar in Hispanic population 31% vs. 32%. Of 124 patients with HIV associated lung cancer with known smoking status, 98% either formerly smoked or were actively smoking and this rate was significantly higher than 86% in HIV negative cohort (P = .0001). Of the 85 patients with known smoking packyears, 75% had higher than 20 packyears of smoking history. HIV associated lung cancer was diagnosed at more advanced stage with 70% having stage 4 disease as opposed to 53% in HIV negative cohort (P = .01). The histology distribution in HIV associated lung cancer was adenocarcinoma 48%, squamous cell carcinoma 19% and small cell lung carcinoma (SCLC) 11%. The histology distribution except the other category was not statistically different between the 2 cohorts.

Table 1.

Demographics and Clinical Characteristics of Lung Cancer Patients With HIV (PWH) Compared to Lung Cancer Patients Without HIV Diagnosed

HIV Positive (N = 174)
(2000-2020)		 HIV Negative (N = 991)
2012-2016		 P value
Age in years, median (IQR) 56.9 (11) 69 (15.5) <.0001
Race/Ethnicity, N (%)a <.0001
 White 11 (9) 243 (27)
 African American 73 (60) 381 (42)
 Hispanic 38 (31) 292 (32)
Sex, N (%) .02
 Male 105 (60) 503 (51)
 Female 69 (40) 488 (49)
Smoking, N (%)a .0001
 No 2 (2) 136 (14)
 Yes 122 (98) 855 (86)
Histology, N (%) .04
 Adenocarcinoma 81 (48) 523 (53)
 Squamous cell carcinoma 32 (19) 220 (22)
 Small cell carcinoma 18 (11) 114 (12)
 Otherb 37 (22) 134 (14)
Stage, N (%)a .01
 Stage I 15 (14) 205 (21)
 Stage II 5 (5) 47 (5)
 Stage III 14 (13) 216 (22)
 Stage IV 76 (70) 523 (53)
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a

Ethnicity unknown: 53 in HIV positive, 75 in HIV negative, Smoking unknown: 50 in HIV positive, stage unknown: 64 in HIV positive.

b

Other histology includes NSCLC, NOS, adenosquamous, large cell carcinoma with neuroendocrine differentiation, pulmonary pleomorphic carcinoma, typical carcinoid.

Three (7%) of HIV associated lung cancer with known EGFR sequencing status (N = 46) harbored activating EGFR mutations. In comparison, of 652 patients diagnosed with lung cancer between 2009 and 2015 in our institution with known EGFR status, 98 patients (15%) was positive for EGFR mutations as we previously reported.30

A subset analysis of SCLC patient in HIV positive (N = 18) and HIV negative cohort (N = 114) also revealed younger age at diagnosis, 56.5 vs. 70 years (P < .005) and predominance of African American patients 58% vs. 29% (P = .017), respectively. Gender, stage, and smoking rates were similar in SCLC cohort.

HIV Characteristics of the Cohort at the Time of Lung Cancer Diagnosis

At the time of lung cancer diagnosis, PWH with known CD4 status (N = 128) had a median CD4 count of 334 cells/μL and 31% of these patients had a CD4 count ≤ 200 cells/μL. Median CD8 count was 835 cells/μL. Of the 109 PWH with known HIV viral load at the time of diagnosis, 63% were virally suppressed with HIV viral load of less than 200 copies/mL. Of the 95 patients with known status, 92% were on antiretroviral therapy at the time of diagnosis (Table 2).

Table 2.

HIV Characteristics and EGFR Mutation Status of HIV Associated Lung Cancer Cohort

HIV Associated Lung
Cancer (N = 174)
(2000-2020)
HIV characteristics
 CD4 count, median (IQR) 334 (465)
 CD4 count <200, N (%) 40 (31)
 CD4 count >200, N (%) 88 (69)
 CD8 count, median (IQR) 835 (724)
 HIV viral load, median (IQR) Undetected (1021)
 HIV viral load <200, N (%) 69 (63)
 HIV viral load >200, N (%) 40 (37)
 ART use, N (%) 87 (92)
EGFR mutation, N (%)
 Present 3 (7)
 Absent 43 (93)
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Screening Patterns in HIV Associated Lung Cancer and HIV Negative Lung Cancer

Lung Cancer screening program was initiated in 2013 in our cancer center after the release of USPSTF lung cancer screening recommendations. Lung cancer screening is facilitated by a dedicated coordinator after a low dose screening lung CT is ordered by primary care providers. We investigated the method of lung cancer diagnosis between 2013 and 2016 after the screening program was established at our institution. The data revealed that only 2 of 34 HIV associated lung cancer patients diagnosed between 2013 and 2016 had been diagnosed through the screening program. Out of 40, 18 patients were eligible for lung cancer screening with the guidelines as they were during this time period. Of eligible patients with HIV associated lung cancer, only 11% were diagnosed through screening. In comparison, in HIV negative cohort during the same time period 2013 to 2016, 175 patients out of 855 patients were found to be eligible for lung cancer screening. Nineteen percent (33/175) of eligible patients were diagnosed with lung cancer through the screening program (P = .42) as we previously reported.31

Immune Biomarkers and Immunotherapy Response in PPW

The tumor PD-L1 expression data was available in 53 HIV associated NSCLC and 29 HIV negative patients with NSCLC diagnosed during a comparable period of time (Figure 1). HIV associated lung cancer had higher rate of PD-L1 negative tumors compared to HIV negative cohort. Results showed that PD-L1 TPS <1% in 60% vs. 31%, TPS 1% to 49% in 22% vs. 34% and TPS ≥ 50% in 20% vs. 34% in HIV associated lung cancer and HIV negative lung cancer patients, respectively (P = .039).

To further investigate potential differences in tumor immune microenvironment of PWH, we assessed tumor-infiltrating lymphocytes when sufficient tissue was available (n = 28) (Figure 2). Three of these patients had SCLC and they were all PD-L1 negative. Only 1 of HIV associated SCLC was virally suppressed. Median CD4 TIL count was 0 cells/10 high power field (hpf) (range 0-1), and median CD8 TIL count was 25 cells/10hpf (range 12-130) in the SCLC cohort.

Figure 2.

Figure 2

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Representative IHC expression of PD-L1, CD4, CD8 T cells in PWH. (A) High PD-L1 expression (B) Low PD-L1 expression (C) Number of tumor infiltrating lymphocytes in tumor biopsies of PWH. Eighteen patients in TPS <1, 4 patients in TPS 1-49 and 3 patients in TPS ≥ 50% (*P < .05 when high PD-L1 group compared to PD-L1 1%-49% and PD-L1 <1%).

Of the 25 patients with HIV associated NSCLC, tumors with high PD-L1 TPS had higher tumor-infiltrating CD8 T cell counts compared to PD-L1 negative and low PD-L1 group (P < .05) while the CD4+ cell counts across PD-L1 groups were not statistically significant (P = .12) (Figure 2). Median CD8 TIL count was 112 cells/10hpf (range 12-878) and median CD4 TIL was 13 cells/10hpf (range 0-316). Interestingly, no clinically meaningful correlation was noted between intratumoral CD4 and CD8 counts and peripheral blood CD4 and CD8 counts (Pearson correlation coefficient R 0.03 and −0.06, respectively). There were no statistically significant differences in CD4 and CD8 TIL counts when comparing virally suppressed patients (HIV viral load <200 copies/mL) to unsuppressed patients or when comparing patients with peripheral CD4 count ≤ 200 cells/μL compared to those with counts >200 cells/μL. These results implicate a relatively “cold” tumor immune microenvironment with low tumor infiltrating lymphocytes, suggesting altered cancer immunosurveillance in PWH.

We further evaluated clinical outcomes in PWH treated with immune checkpoint inhibitors (either alone or in combination with chemotherapy) (n = 19 patients in total; n = 13 with metastatic NSCLC). Of the 13 patients with metastatic NSCLC, 23% (3 of 13) patients achieved partial response by RECIST criteria (Table 3). Two of these patients received chemoimmunotherapy, while 1 patient was treated with single-agent immunotherapy. Four patients achieved stable disease, adding up to 54% of the disease control rate. There were no new safety signals detected in PWH. One patient who developed grade 3 ICI-related necrotizing myositis requiring hospitalization and another patient who experienced grade 2 ICI-related dermatitis requiring steroid treatment. Median peripheral CD4 count was found to be numerically lower after immunotherapy, 409 cells/μL (IQR 370) at baseline vs. 290 cells/μL (IQR 298) while all patients remained virally suppressed.

Table 3.

Treatment and Response Details of Patients With HIV Associated Lung Cancer Treated With Immunotherapy

HIV Associated Lung
Cancer Treated With
Immunotherapy
(N = 19)
Metastatic NSCLC
Treatment type, N (%)
 Chemoimmunotherapy 7 (54)
 Single agent immunotherapy 6 (46)
Response, N (%)
 POD 6 (46)
 PR 3 (23)
 SD 4 (31)
Locally advanced NSCLC
Treatment type, N (%)
 Consolidation immunotherapy 4 (100)
Response, N (%)
 Remission 4 (100)
Small cell lung cancer
Treatment type, N (%)
 Chemoimmunotherapy 1 (50)
 Dual agent immunotherapy 1 (50)
Response, N (%)
 POD 2 (100)
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Discussion

In this study focused on a large urban cohort of HIV associated lung cancer, we make several important observations that may impact healthcare policies and clinical management. In our cohort, patients with HIV associated lung cancer were diagnosed about 10 years younger than the general lung cancer patient population, often at an advanced stage. Our study demonstrates the enrichment of African Americans in the HIV associated lung cancer population compared to lung cancer patients without HIV diagnosis, which is similar to prior studies.32 In comparing HIV associated SCLC to HIV negative SCLC, we observed a recurring pattern of diagnosis at younger age and a predominance of African American patients. This result is likely due to the increased incidence of HIV in minorities and reinforces the racial disparities in the healthcare system.33 Racial disparities, particularly among African Americans and Hispanic population, has been demonstrated to contribute to the lower rates of lung cancer screening and guideline concordant management.34,35 Concerted efforts must be undertaken to address these health inequities.

The early age at diagnosis which disqualifies many for screening in addition to the low screening rates in the eligible population also contribute to the diagnosis at an advanced stage in PWH. Despite the decreased age cut off (50 years) and pack years (20 packyears) in the US Preventive Services Task Force (USPSTF) lung cancer screening criteria in 2021, which expands the eligible population significantly, these criteria remain short in detecting lung cancer in PWH at early stages. In our study, the rate of eligible PWH who were diagnosed with lung cancer as part of routine screening based on the USPSTF guidelines of between 2013 to 2016 was numerically lower than the rates in HIV-negative cohort. 20% (8/40) of the PWH cohort were not eligible for lung cancer screening solely due to the age cut off. The optimal lung cancer screening criteria in PWH should be investigated in larger cohorts as this population may benefit from a lower age cut off. In addition, rigorous implementation of lung cancer screening practices, especially for vulnerable, high-risk populations like PWH, can significantly mitigate the mortality and morbidity associated with lung cancer.

Our study, in line with the literature, demonstrates a higher rate of tobacco use in HIV associated lung cancer compared to patients without an HIV diagnosis.32 Smoking cessation is another powerful lung cancer risk mitigation approach in this population since smoking remains a significant contributor to the development of lung cancer in PWH.

T cell dysregulation contributes to the incidence of cancer and may also have implications on immunotherapy. In uncontrolled HIV, the depletion of CD4+ T cells facilitate the proliferation of virus infected cells, ultimately promoting the development of virus associated cancers. Even when CD4 counts are within normal range, chronic antigen exposure in HIV infection leads to the transformation of T cells to an exhausted state with higher expression of immune checkpoints like PD-1. This change contributes to impairment in function and proliferation of T cells.36 In addition, T cell receptor diversity is perturbed in HIV infection with most studies reporting decreased TCR repertoire with uncontrolled HIV infection.37 It has been demonstrated that adequate viral suppression with antiretroviral therapies is not sufficient to restitute TCR repertoire.38The distribution of TILs in our study in comparison to the peripheral lymphocyte count and HIV control, provides intriguing insights that may be connected to the altered immune regulation in PWH.

In our study, it is worth noting that 31% of HIV associated lung cancer had peripheral CD4 counts below 200 cells/μL. This underscores the vital importance of improving access to and adherence to anrtiretroviral therapy. Prevention and early diagnosis is crucial since HIV associated lung cancer has similar survival outcomes matched HIV negative lung cancer population when treated with the same standard of care.39

Our study demonstrates that PWH generally exhibit lower PD-L1 scores when compared to HIV negative cohort. This is interesting since several studies reported higher PD-L1 score27,40,41 while 1 study reported lower PD-L1 expression in PWH.26 This difference in PD-L1 expression is not related to HIV viral suppression since the rates are similar across these studies. It is worth noting that the studies reporting higher PD-L1 score in PWH used a different PD-L1 antibody, E1L3N as opposed to the 22C3 antibody used in our study.40,41 While this difference may contribute to the contrast to some extent, it is important to acknowledge that multiple studies have demonstrated high concordance between E1L3N and 22C3 in detecting PD-L1 in NSCLC cohorts, suggesting this may not be the primary factor driving the observed differences.42,43 Variations in race/ethnicity, histology and stage at diagnosis can contribute to discrepancies between studies. Our cohort was diagnosed at a more advanced stage compared to the other studies reporting higher PD-L1.40,44 In addition, our study includes a higher percentage of adenocarcinoma patients tested for PD-L1 expression. Therefore, the lower percentage of squamous cell carcinoma in our cohort may account for the decreased PD-L1 positivity in our study compared to El Zarif et al.27 Additionally, racial differences may be contributing since the majority of our cohort is composed of African American (60%) and Hispanic (31%) patients in contrast to 44% of African American and 8.5% of Hispanic population reported in El Zarif et al.27

We documented higher CD8+ TILs in HIV associated lung cancer with high PD-L1 expression which is corroborated in other studies of HIV unknown NSCLC.45,46 High TILs have been suggested as prognostic and predictive of immunotherapy response markers in NSCLC.47,48 In line with the observed low expression of PD-L1 in our HIV positive cohort, we also noted a low median CD8 TIL count of 112 cells/10hpf in our study. This count stands in contrast to the literature data for NSCLC of HIV unknown status which typically ranges from 250 to 1050 cells/10hpf (considering 1 mm2 is roughly equivalent to 5 hpf) .45,49 Interestingly, in our study, the number of CD4+ and CD8+ TILs does not correlate with the peripheral CD4 and CD8 lymphocyte counts. We were also unable to find a statistical difference between the intratumoral TILs and PWH who had achieved viral suppression or had high CD4 counts, possibly due to the limited sample size. It is also possible that the T cell dysregulation seen in PWH might influence the tumor immune microenvironment, independent of their HIV control status. Despite lower PD-L1 expression, our cohort achieved a partial response of 23% and there were no safety signals detected for immunotherapy.

Conclusions

Our cohort study describing one of the largest PWH populations with lung cancer demonstrates multiple unique clinicopathologic features, including younger age at diagnosis, higher rates of African Americans, and advanced stage at presentation compared to the overall patient population with lung cancer. These results demonstrate the need for dedicated screening measures to reduce the morbidity and mortality of lung cancer in this population. Low PD-L1 expression was noted in the majority of patients with HIV associated lung cancer in our cohort; however, some of these patients still derived benefit from immune checkpoint inhibitor therapy. These findings suggest unique immune biology in PWH and warrant further studies investigating the tumor immune microenvironment and complexities of immunotherapy response in this high-risk population.

Clinical Practice Points.

Lung cancer in PWH poses a distinctive challenge, as its prevalence increases with the extended survival provided by highly effective antiretroviral therapies. The impact of HIV on cancer immunosurveillance remains an area of active investigation. A better understanding of the tumor immune microenvironment in HIV associated lung cancer is imperative for enhancing patient outcomes. Our study highlights the need for a specialized lung cancer screening program in PWH, given the tendency for diagnosis at a younger age and with more advanced disease. Additionally, our findings suggest a relatively “cold” tumor immune microenvironment characterized by low levels of tumor infiltrating lymphocytes, indicating potential alterations in cancer immunosurveillance among PWH. Despite the limited expression of PD-L1, immunotherapy demonstrated favorable tolerability and achieved reasonable disease control in our cohort. Future studies focusing on PWH are warranted to optimize early diagnosis and improve clinical outcomes.

Acknowledgments

This work was supported by P30 Cancer Centers Support Grants (CCSG) (grant number 3P30CA013330-48S1) and AECC Price Pilot Project Award.

Footnotes

Disclosure

B. H. has grants or contracts from Boehringer Ingelheim, Astra Zeneca, Merck, BMS, Advaxis, Amgen, AbbVie, Daiichi, Pfizer, GSK, Beigene, Janssen, received consulting fees from Astra Zeneca, Boehringer Ingelheim, Janssen, Takeda, Merck, BMS, Genentech, Pfizer, Eli-Lilly, Arcus, Merus, BMS and participates in data safety monitoring or advisory boards of TPT, BMS, Apollomics, Nuvalent, Merck. M. H. received consulting fees from Astra Zeneca, Blueprint Medicines, Jazz Pharmaceuticals, Takeda Pharmaceuticals and honoraria from Coherus Biosciences.

CRediT authorship contribution statement

Ayse Ece Cali Daylan: Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing, Formal analysis, Visualization. Catarina Martins Maia: Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing, Validation, Visualization. Shirin Attarian: Investigation, Methodology, Writing – review & editing. Xiaoling Guo: Investigation, Methodology, Writing – review & editing. Mindy Ginsberg: Investigation, Methodology, Writing – review & editing. Rasim Gucalp: Conceptualization, Methodology, Writing – review & editing. Missak Haigentz: Conceptualization, Methodology, Writing – review & editing. Balazs Halmos: Conceptualization, Methodology, Writing – review & editing. Haiying Cheng: Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Writing – review & editing.

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