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. Author manuscript; available in PMC: 2023 Nov 1.
Published in final edited form as: Ann Oncol. 2022 Aug 10;33(11):1159–1167. doi: 10.1016/j.annonc.2022.07.1942

Association of Tumor-infiltrating Lymphocytes (TILs) with Survival Depends on Primary Tumor Sidedness in Stage III Colon Cancers (NCCTG N0147) [Alliance]

B Saberzadeh-Ardestani 1, N R Foster 2,3, H E Lee 4, Q Shi 2,3, S R Alberts 5, T C Smyrk 4, F A Sinicrope 1,5
PMCID: PMC9882989  NIHMSID: NIHMS1866525  PMID: 35963480

Abstract

Background:

Tumor-infiltrating lymphocytes (TILs) are a robust and independent prognostic variable in localized colon cancer. Given reported differences in molecular features and prognosis of right- versus left-sided tumors, we examined the association of TIL densities with patient survival by primary tumor sidedness in stage III cancers, including clinical low- (T1–3, N1) and high-risk (T4 and/or N2) groups.

Patients and methods:

In a phase III trial of FOLFOX-based adjuvant chemotherapy, TIL densities were analyzed and dichotomized in colon carcinomas (N=1532) based on a previously determined cutpoint optimized for disease-free survival (DFS). Right-sided tumors were defined as proximal to the splenic flexure. Associations of TILs and sidedness with 5-year DFS were examined using Kaplan-Meier methodology along with multivariable modeling and relative contribution analysis by Cox regression.

Results:

Lower TIL densities were found in left- vs right-sided tumors (P<0.0001). The association of TIL densities with DFS differed significantly by tumor sidedness (Pinteraction= .045). Overall, patient tumors with low (vs high) TILs had significantly poorer DFS in right-sided [HR=2.02 (95%CI: 1.45–2.82); Padj<0.0001], but not left-sided tumors (Padj=0.1731). Among clinical low-risk patients, low (vs high) TILs were adversely prognostic only in right-sided tumors (Padj=0.0058). Among high-risk patients, low TILs were prognostic independent of sidedness (Padj<.025). The relative contribution of TILs to DFS was substantially greater in right- vs left-sided tumors (24% vs 1.5%). In high-risk tumors, TILs had the highest relative contribution to DFS (42%) of all variables. In low-risk tumors, the contribution of TILs (16%) to DFS was second to KRAS.

Conclusions:

The association of TIL densities with patient survival differed by primary tumor sidedness and clinical risk group, suggesting that TILs should be interpreted in this context among stage III colon cancers.

ClinicalTrials.gov Identifier:

NCT00079274

Keywords: Tumor-infiltrating lymphocytes, Colonic Neoplasms, Primary Tumor Site, Prognosis, Adjuvant Chemotherapy

Introduction

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States.1 Identifying patients who are more likely to have disease recurrence and metastasis after surgical resection is a major unmet need. Tumor-infiltrating lymphocytes (TILs) reflect the host anti-cancer immune response.2, 3 In multiple studies in nonmetastatic CRC, TIL density in the tumor microenvironment (TME) has been shown to be a statistically significant and independent predictor of patient survival.4, 5 TIL densities are typically increased in tumors with deficient DNA mismatch repair (dMMR) which are more commonly located in the right colon.4, 6, as are tumors harboring BRAFV600E point mutations and the CpG island methylator phenotype.7, 8 Furthermore, differences in immune-related gene expression and tumor transcriptomic profiles, including consensus molecular subtypes (CMS), are observed in relationship to primary tumor sidedness.9 10 Primary tumor sidedness has become of much scientific interest given that it’s a source of biological heterogeneity and the finding that colon cancer prognosis11, 12 and response to treatment can differ by anatomic tumor location.13 In this regard, clinical benefit of anti-epidermal growth factor receptor (EGFR) antibody therapy in patients with metastatic CRC was limited to tumors of the left colon.13

We quantified TIL densities in colon cancers and determined whether their association with patient prognosis differs by primary tumor sidedness. Toward this objective, we examined the interaction between TIL densities and tumor sidedness in relationship to disease-free survival (DFS) in patients with stage III colon cancers treated in a phase 3 clinical trial of adjuvant FOLFOX-based chemotherapy (North Central Cancer Treatment Group [NCCTG] N0147). We also studied the association of TILs with DFS by sidedness in clinical low-risk (T1–3, N1) and high-risk (T4 and/or N2) groups that are used to guide the recommended duration of adjuvant treatment with a fluoropyrimidine plus oxaliplatin in patients with stage III colon cancers.14

Method

Study Population

Patients with resected stage III colonic adenocarcinomas had been treated for 6 months in a phase 3 clinical trial of adjuvant mFOLFOX6 chemotherapy with or without cetuximab (NCCTG N0147).15 No difference in patient outcome was seen by study arm,15 which allowed pooling of the data from both arms. TIL data was generated on a subset (N=1532) of patients based on tissue availability and cases are representative of the parent cohort. Use of tissue specimens and clinical data from the N0147 trial was approved by the Mayo Clinic Institutional Review Board. The parent clinical trial was conducted by the NCCTG (now part of Alliance for Clinical Trials in Oncology), and each participant signed an informed consent.

TILs and Sidedness

TIL densities in tumor tissues were determined by manual counting in routine histologic sections from surgical resections, as previously described.2 TIL densities were dichotomized (≤3/HPF) based on a previously determined cut-off that was shown to best separate patients for DFS in the study cohort.2 Primary tumor site was categorized as right-sided for cancers located proximal to the splenic flexure, or left-sided. Covariates included age (years), sex (female vs male), race (white vs others), Eastern Cooperative Oncology Group performance status (PS; 0 vs 1/2),16 tumor grade (high vs low), T stage (T1/T2 vs T3/T4), number of positive lymph nodes (LNs) (1–3 vs ≥4), risk group (low [T1–3, N1] vs high [T4 and/or N2]), DNA mismatch repair (MMR) (deficient MMR vs proficient MMR), KRAS (nonmutated vs mutated), BRAFV600E (present or absent). Methodologies used to determine MMR status and the mutational status of KRAS and BRAFV600E were described previously.2

Statistical Analysis

The primary study outcome was DFS, which was defined as the time from randomization to the first of either disease recurrence or death. The association of the dichotomous TILs and other covariates with tumor site was evaluated using the chi-square test. A Kaplan-Meier methodology17 and multivariable Cox regression model18 were used to analyze DFS by TILs and sidedness with adjustment for covariates including, age, PS, T/N stage, histologic grade, KRAS, BRAF, MMR and treatment arm. Adjusted hazard ratios (HRadj) and 95% confidence intervals (CI) are reported. Two-sided P-values are reported and P-values <0.05 were considered statistically significant for all analyses. SAS version 9.4 (SAS Institute, Cary NC) was utilized. The proportional hazards (PH) assumption was tested and found to be met in multivariable models from our study cohort (a priori p < 0.01 for variable to violate PH assumption given sample size). Data collection and statistical analyses were conducted by the Alliance Statistics and Data Management Center. All analyses were based on the study database frozen on [August 5, 2015]. The relative contribution of each variable to DFS was calculated using χ2 from Harrell’s rms R package (version 3.2.3; http://biostat.mc.vanderbilt.edu/rms) based on multivariable Cox regression models.

Results

Patient characteristics

Within our study cohort of 1532 patients, 783 (51%) had right-sided tumors, 731 (48%) had left-sided cancers, and 18 (1%) had missing data for tumor site. Mean patient age was 58 years (SD of 11 years) with a range of 19–86 years. Median patient follow-up time was 83 months. Patient characteristics stratified by primary tumor sidedness are shown in Table 1. Low TIL densities were significantly more common in patients with left-sided vs right-sided cancers (80% vs 68%, P<0.0001), which was maintained when the cohort was limited to pMMR tumors (81% vs 75%, P=0.025). A higher prevalence of high-grade tumors (P<0.0001) and those with mutations in KRAS (P=0.0005), BRAFV600E (P<0.0001) or dMMR (P<0.0001) were found in right-vs left-sided tumors. These differences remained statistically significant when restricting the cohort to tumors with pMMR (all P<0.0001). Neither T nor N stage nor risk groups (high, low) differed significantly based on tumor sidedness (Table 1).

Table 1.

Clinicopathological and molecular features of patients stratified by primary tumor site.

Variablesa,b Total (N=1532) Tumor site P-value
Right-sided (N=783) Left-sided (N=731)
Age, years N (%) <0.0001c
 <50 327 (21%) 129 (16%) 193 (26%)
 ≥50 1205 (79%) 654 (84%) 538 (74%)
Sex, N (%) 0.2148c
 Female 732 (48%) 387 (49%) 338 (46%)
 Male 800 (52%) 396 (51%) 393 (54%)
Race, N (%) 0.4181c
 White 1349 (89%) 696 (89%) 639 (87%)
 Non-white 163 (11%) 78 (11%) 82 (13%)
T stage, N (%) 0.0533c
 T1 or T2 226 (15%) 103 (13%) 122 (17%)
 T3 or T4 1306 (85%) 680 (87%) 609 (83%)
N stage, N (%) 0.8210c
 N1 (1–3 nodes) 906 (59%) 464 (59%) 429 (59%)
 N2 (≥4 nodes) 626 (41%) 319 (41%) 302 (41%)
Risk group, N (%) 0.9276c
 Low (T1–3, N1) 804 (53%) 411 (53%) 382 (52%)
 High (T4 and/or N2) 728 (47%) 372 (47%) 349 (48%)
Histologic grade, N (%) <0.0001c
 Low 1152 (75%) 533 (68%) 606 (83%)
 High 380 (25%) 250 (32%) 125 (17%)
Performance status, N (%) 0.0884c
 0 1161 (76%) 579 (74%) 568 (78%)
 1/2 371 (24%) 204 (26%) 163 (22%)
KRAS, N (%) 0.0005c
 Nonmutated 968 (64%) 462 (60%) 493 (69%)
 Mutated 536 (36%) 307 (40%) 224 (31%)
BRAFV600E, N (%) <0.0001c
 Absent 1262 (86%) 574 (77%) 671 (96%)
 Present 198 (14%) 169 (23%) 28 (4%)
MMR status, N (%) <0.0001c
 dMMR 153 (10%) 137 (18%) 13 (2%)
 pMMR 1357 (90%) 635 (82%) 708 (98%)
TILs, N (%) <0.0001c
 Low (≤3/HPF) 1132 (74%) 534 (68%) 584 (80%)
 High (>3/HPF) 400 (26%) 249 (32%) 147 (20%)
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dMMR, deficient mismatch repair; pMMR, proficient mismatch repair; TILs, tumor-infiltrating lymphocytes.

a

Missing values are not included in the percentages.

b

Sum of the numbers from each subcategory may not equal the total reported cases due to missing values.

c

Chi-square test.

Association of TILs and sidedness with disease-free survival (DFS)

In the overall cohort, patients whose tumors showed low vs high TILs had significantly poorer DFS [HRadj 1.74 (95%CI, 1.35–2.24); Padj<0.0001] (Table 2) that was also seen when the cohort was limited to pMMR tumors [HR 1.65 (95%CI, 1.25–2.16); Padj=0.0002]. We found an interaction between TILs and sidedness, but not other variables, for DFS that was statistically significant after adjustment for covariates (Pinteraction(adj) =0.045)[Supplementary Table 1]. Accordingly, we compared DFS rates by TILs and sidedness and found that low (vs high) TILs was significantly associated with poorer DFS in right-sided [HRadj 2.02 (95% CI, 1.45–2.82); Padj<0.0001, 5 yr DFS 57% vs 77%], but not in left-sided tumors [HRadj 1.30 (95%CI, 0.88–1.92); Padj=0.173, 5 yr DFS 69% vs 76%] (Figure 1). Analysis based on clinical risk group revealed similar results whereby low risk tumors had significantly poorer DFS for low vs high TILs that was limited to right-sided cancers (Padj=0.0058). Among high risk tumors, however, low vs high TILs were associated with significantly poorer DFS irrespective of sidedness (right: Padj=0.0004 vs left: Padj=0.0244) (Table 2).

Table 2.

Disease–free survival for colon cancer patients stratified by TILs and sidedness among overall population, high and low risk cases.

Population Tumor site HRadj (95%CI)¥ 5-year DFS P adj
Low TILs High TILs
Overall Right 2.02 (1–45–2.82) 57% 77% <0.0001
Left 1.30 (0.88–1.92) 69% 76% 0.1731
Overall 1.74 (1.35–2.24) 63% 77% <0.0001
Low risk (T1–3, N1) Right 2.07 (1.20–3.56) 70% 84% 0.0058
Left 1.03 (0.60–1.76) 78% 79% 0.9135
Overall 1.52 (1.04–2.23) 74% 81% 0.0264
High risk (T4 and/or N2) Right 2.05 (1.34–3.13) 44% 68% 0.0004
Left 1.86 (1.04–3.32) 60% 71% 0.0244
Overall 2.00 (1.43–2.81) 53% 69% <0.0001
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TILs, tumor-infiltrating lymphocytes; DFS, disease-free survival

¥

Age, Performance status, T-stage, N-stage, Histological grade, KRAS, BRAS, Mismatch repair status and treatment arm were used in adjustment of hazard ratio.

Figure 1.

Figure 1.

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Association of TILs and DFS for stage III colon cancer patients in overall cohort and by clinical risk group. Left-sided tumors in overall cohort (left panel); Right-sided tumors in overall cohort (right panel).

Given the observed interaction between TILs and sidedness, we examined their combined variable (4 groups: TIL low/right-sided, TIL low/left-sided; TIL high/right-sided, TIL high/left-sided) in relationship to DFS. Patients with TIL low/right-sided tumors had the poorest DFS in the overall cohort [HRadj 2.12 (95%CI, 1.53–2.95); Padj<0.0001 vs reference] (Figure 2A) and when the cohort was restricted to pMMR tumors [HRadj 2.05 (95% CI, 1.40–3.01); Padj=0.0003]. Analysis by clinical risk group was then performed. In both low risk and high risk groups, TIL low/right sided tumors had the poorest DFS [low risk: HRadj 2.09 (95%CI, 1.23 –3.55), Padj=0.0402, (Figure 2B); high risk: HRadj 2.14 (95%CI, 1.41–3.27), Padj<0.0001, (Figure 2C)]. Importantly, similar outcomes were seen for low risk tumors that were TIL low/right-sided (5 yr DFS: 70%) and for high risk tumors with TILs high irrespective of sidedness (5-yr DFS: right, 68%; left, 71%).

Figure 2.

Figure 2.

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Kaplan–Meier estimates of disease–free survival for colon cancer patients with TIL high/right-sided, TIL high/left-sided, TIL low/right-sided, TIL low /left-sided. (A) overall population; (B) low risk patients [T1–3, N1], (C) high risk patients [T4 and/or N2].

A forest plot was constructed based on results of multivariable regression analysis of TIL/sidedness and other tumor-related variables associated with DFS in the overall patient population (Table 3). In the overall cohort, TIL/sidedness as well as T stage, N stage, and KRAS were each significantly and independently associated with patient DFS. We have previously shown that the association of BRAFV600E with clinical outcome is attenuated by the enrichment for BRAFV600E in dMMR tumors in patients.19, 20 A similar multivariable analysis in clinical low and high risk group was performed as shown in Table 4. While low TILs and KRAS mutation were adversely prognostic in both risk groups, dMMR vs pMMR was only prognostic in high risk tumors where it was associated with poorer DFS. Multivariable models were also adjusted for study treatment arm (cetuximab-containing vs control). To further support our findings, we generated minimally adjusted multivariable models that included MMR or TILs along with covariates (age, T stage, N stage, histologic grade, PS) [data not shown]. In these models, we found that in contrast to MMR, TILs were significantly associated with DFS indicating that TILs are a more robust prognostic variable.

Table 3.

Forest plot based on results of multivariable analysis of tumor-related variables associated with DFS in the overall patient population.

graphic file with name nihms-1866525-t0001.jpg
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dMMR, deficient mismatch repair; pMMR, proficient mismatch repair; TILs, tumor-infiltrating lymphocytes; PS, performance status; WT, wild-type.

Table 4.

Forest plot based on results of multivariable analysis of tumor-related variables associated with DFS in clinical low risk (T1–3, N1) and high risk (T4 and/or N2) groups.

graphic file with name nihms-1866525-t0002.jpg
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dMMR, deficient mismatch repair; pMMR, proficient mismatch repair; TILs, tumor-infiltrating lymphocytes; PS, performance status; WT, wild-type.

Analysis of the relative contribution (%) of each variable to DFS was then examined multivariately. In the overall population, the top three contributors to DFS were N stage (44%), TILs (15%), and KRAS mutation (14%). The relative contribution of TILs to DFS was substantially greater in right-sided tumors (right: 24% vs left: 1.5%) and was only exceeded by N stage (Figure 3 A, B). Among low risk tumors, the relative contribution of TILs to DFS (16%) was second only to KRAS status (Figure 3 C). For high risk tumors, TILs had the highest relative contribution to DFS (42%) followed by tumor sidedness (14%) [Figure 3 D].

Figure 3.

Figure 3.

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Relative contributions (%) of the variables in multivariable Cox models for prediction of DFS in (A) left-sided and (B) right-sided tumors in the overall cohort; and patients categorized into clinical (C) low risk and (D) high risk groups.

Discussion

Based on reported differences in immune cell composition, molecular subtypes, and microbial composition by anatomic tumor location,7, 21–23 we analyzed TIL densities and their association with DFS based on tumor sidedness. Consistent with prior studies by ourselves and others, we found significantly higher TIL densities in right- versus left-sided tumors. Moreover, a low vs high TIL density was significantly and independently associated with poorer DFS in patients with stage III colon cancers.2–4, 24, 25 In contrast to MMR that was not prognostic in the overall cohort, TILs were significantly associated with DFS multivariately indicating that TILs are a more robust prognostic variable. Next, we demonstrated that the association of TIL densities with DFS differed significantly by primary tumor sidedness. Specifically, low TIL densities were predictive of significantly poorer DFS in right-sided, but not left-sided cancers after adjustment for KRAS/BRAF, MMR status, and other covariates. Given the significant interaction found between TILs and sidedness, we then examined their combined variable in relationship to DFS and found that patients with low TIL/right-sided tumors had the poorest DFS in the overall cohort and in both clinical risk groups. Within each clinical risk group, the combined variable was able to prognostically stratify patients. In clinical high (vs low) risk patients, those with TILs low/right-sided tumors had markedly shorter 5-year DFS (44% vs 70%). Furthermore, patient tumors with high TILs of either anatomic location had similarly favorable survival rates. Of note, no difference was observed between TILs and DFS by treatment arm overall or in left-sided tumors from the N0147 or PETACC-8 clinical trial cohorts,26 in contrast to prior data demonstrating the predictive utility of tumor sidedness for response to anti-EGFR therapy in metastatic CRC.13

Our observation that low TIL/right-sided tumors had the poorest DFS in the overall cohort and in clinical risk groups deserves comment. We found higher TIL densities in right- versus left-sided tumors (even after exclusion of dMMR cancers) and in a prior study in the N0147 cohort, increased TILs included CD3+ and cytotoxic CD8+ T lymphocytes.3 Gene expression data have also shown that right- versus left-sided colon cancers have increased immune cells with enhanced cytotoxic function and interferon-Ɣ signatures shown to activate innate immunity and inhibit tumorigenesis.27, 28 Potentially, higher TIL densities including cytotoxic T-cells may be needed to overcome an immunosuppressive TME in the right colon. We found that BRAFV600E and KRAS mutations were more common in the right colon and both of these oncogenes have been shown to promote an immunosuppressive TME.29–31 Interestingly, the association of FOXP3+ regulatory T-cells (Tregs) with poor survival was restricted to colon cancers with low CD4+ or low cytotoxic CD8+ T-cells infiltration.32, 33 While Tregs can suppress inflammation and promote better outcome in colon cancer, they were shown to suppress anti-tumor immunity with expression of RORƳt.34 Another factor shown to differ by tumor sidedness that contributes to biological heterogeneity is the gut flora35–38 which can modulate anti-tumor immunity.21, 22, 39 A potential contributor to immune suppression in the TME of the right colon is the anaerobic bacterium Fusobacterium nucleatum whose DNA content was shown to be significantly increased in right- vs left-sided colon cancers35 where it was inversely related to CD3+ T-cell density.36, 37 F. nucleatum has also been shown to be associated with adverse outcome in patients with CRC.40, 41

We examined the relative contribution of TILs for the prediction of patient DFS. In the overall cohort, TILs were second only to N stage for prediction of DFS and their relative contribution was substantially greater, i.e., 16-fold, in right- vs left-sided cancers. Analysis by clinical risk group revealed that TIL density had the highest relative contribution to DFS among high risk tumors that was followed by sidedness. Among low risk tumors, TILs were second to KRAS then followed by MMR for prediction of DFS.

Strengths of this study include same stage patients from a well-characterized clinical trial cohort with mature survival data. While our findings await validation, we studied a relatively large clinical trial cohort of well annotated cases with meticulous documentation of patient outcomes. Limitations include the fact that all patients received adjuvant chemotherapy for 6 months such that predictive utility of TILs for chemotherapy outcomes could not be studied. In conclusion, patient tumors with low TILs and right-sided location had the poorest DFS in the overall cohort and within clinical risk groups. If validated in a separate clinical trial cohort, these findings suggest that TIL densities should be interpreted in the context of tumor site for prognostication.

Supplementary Material

1

Highlights.

  • Association of TIL densities with 5-year DFS differed significantly by primary tumor sidedness.

  • Overall, low vs high TILs were significantly associated with poorer DFS among right-sided, but not left-sided tumors.

  • Prognostic impact of TILs was limited to right-sided cancers among clinical low risk tumors.

  • Relative contribution of TILs to DFS was greater in right- vs left-sided tumors (24% vs 1.5%).

  • In clinical high-risk tumors, TILs had the highest relative contribution to DFS of all variables.

Support

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Awards Numbers R01 CA210509 (to FAS), U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), and UG1CA232760. Also supported in part by funds from Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://acknowledgments.alliancefound.org.

Footnotes

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Conflict of interest statement

The authors report no relevant conflicts of interest related to the content of this manuscript.

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