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. Author manuscript; available in PMC: 2020 Sep 15.
Published in final edited form as: J Immunol. 2020 Feb 12;204(6):1431–1435. doi: 10.4049/jimmunol.1901172

Anti-tumor immunity by pathogen-specific CD8 T cells in the absence of cognate antigen recognition

Derek B Danahy *,†, Roger B Berton *,†, Vladimir P Badovinac *,†,#
PMCID: PMC7310247  NIHMSID: NIHMS1598772  PMID: 32051220

Abstract

Cancer prognosis often correlates with the number of tumor-infiltrating CD8 T-cells, but many of these cells recognize pathogens that commonly infect humans. The contribution of pathogen-specific ‘bystander’ CD8 T-cells to antitumor immunity remains largely unknown. Inflammatory cytokines are sufficient for memory CD8 T-cell activation and gain of effector functions, indicating tumor-derived inflammation could facilitate pathogen-specific CD8 T-cells to participate in tumor control. Here, we show in contrast to tumor-specific CD8 T-cells, pathogen-specific primary memory (1°M) CD8 T-cells inside tumor were not able to exert their effector functions and influence tumor progression. However, infection-induced memory CD8 T-cells with defined history of repeated Ag-encounters (i.e. quaternary memory, 4°M), showed increased sensitivity to tumor-derived inflammation that resulted in activation, gain of effector functions and better control of tumor growth. Thus, memory CD8 T-cells with heightened ability to recognize environmental inflammatory stimuli can contribute to antitumor immunity in the absence of cognate Ag-recognition.

Introduction

Activated CD8 T cells that recognize tumor Ags can exert their effector functions and improve the outcome of cancer development (1, 2). Infiltration of tumors by CD8 T cells correlates with a positive prognosis in patients (3, 4). However, many CD8 T cells that infiltrate human tumors recognize pathogens that frequently infect humans and have no defined role in antitumor immunity (5-7). These ‘bystander’ memory CD8 T cells were recently repurposed by therapeutically administering pathogen-associated Ags in the tumor environment to promote effector functions and improve cancer prognosis (6). However, inflammatory cytokines are sufficient to elicit effector functions such as IFN-γ production in bystander CD8 T cells, suggesting that tumor-infiltrating memory CD8 T cells (CD8 TILs) may not require cognate Ag recognition to become activated, perform effector functions, and improve host outcome (8, 9).

Pathogen-specific memory CD8 TILs were shown to have low/undetectable Ag-independent responses in B16 melanoma suggesting their inability to contribute to antitumor immunity (6). However, recently we have shown that phenotype and function of memory CD8 T cell populations is influenced by their history of Ag-encounters (10, 11). Specifically, secondary to quaternary memory (2°M-4°M) CD8 T cells have increased sensitivity to inflammatory cytokines resulting in a more vigorous bystander activation compared to primary memory (1°M) counterparts (12). Importantly, multiple stimulated memory CD8 T cells may also reflect the biology of tumor-infiltrating bystander CD8 T cell responses generated in response to pathogens that frequently infect/re-infect humans (e.g., EBV and CMV) (6). Thus, although bystander memory CD8 T cells can provide protection to unrelated infections (13, 14) it is unknown if they can have a discernable role in antitumor immunity.

Materials and Methods

Mice, cell lines, and tumor monitoring

C57BL/6, TCR-Tg P14, and TCR-Tg OT-I mice were bred and maintained at University of Iowa animal facilities at the appropriate biosafety level according to the University of Iowa Animal Care and Use Committee and NIH guidelines. Male and female mice >6 weeks old were used in experiments; results were similar in both. B16-OVA was obtained from Dr. Lyse Norian (University of Alabama at Birmingham, Birmingham, AL). B16 cells were grown in DMEM with 4.5g/L D-glucose, L-glutamine, 10% fetal calf serum (HyClone Laboratories) and supplementum complementum (made in-house). Cell lines were passaged every 2-3 days and/or when cell confluency was greater than 80% in 75cm2 tissue culture flask (DOT Scientific). Cells were not sequentially passaged longer than 3 weeks. In vitro and in vivo tumor growth did not vary considerably throughout the study. For implantation, 2×104 B16 cells were injected s.c. in the hind flank at 100μL volume with equal parts B16 medium and Matrigel Matrix #356234 (Corning), as performed previously (15, 16). Tumor progression was determined by measuring tumor length multiplied by width using an electronic digital caliper. Mice were sacrificed upon reaching any animal protocol threshold including tumor length of >15mm or tumor ulceration. Weight loss and survival of mice were monitored to determine disease progression.

Generating Ag-experienced CD8 T cells

Mice received 104 naïve Thy disparate P14 or OT-I CD8 T cells prior to infection. Attenuated wild-type DPL1942 and recombinant L. monocytogenes expressing ovalbumin and glycoprotein 33 (LM or LM-OVA/GP33, respectively) strains were injected i.v. at 1×107 CFU/mouse. Virulent LM strain 10403s was injected i.v at 1×106 CFU/mouse. LCMV Armstrong was injected i.p. at 2×105 PFU/mouse.

Cell isolation, fluorescent labeling, and flow cytometric analysis

Spleen samples were mashed through a 70μm filter with the plunger flange of a 1mL syringe. Splenocytes were treated with ACK lysis buffer for 3 minutes. Tumors were cut into small pieces and placed in DMEM medium +10% FCS + Supplementum Complementum + 0.8mg/mL Collagenase type I (Worthington) + 60U/mL of DNase and placed in a 37°C shaker at 300RPM for 45-60 minutes, as performed previously (15, 16). Tumor samples were mashed through a 70μm cell strainer using the plunger flange of a 1mL syringe and cell suspensions treated with ACK. After washing, samples were filtered through a 70μm cell strainer one additional time prior to antibody labeling in 96-well flat bottom plates. Cells were labeled with the following fluorescently-labeled mAb: CD8α (53-6.7), CD69 (H1.2F3), PD-1 (J43), IFN-γ (XMG1.2), Thy1.1 (HIS51), Thy1.2 (53-2.1), Granzyme B (QA16A02), KLRG1 (2F1), CD62L (MEL-14). Samples requiring intracellular labeling were subsequently treated with Cytofix/Cytoperm (BD Biosciences) for 10 minutes at 4°C and washed in Perm/Wash (BD Biosciences) before intracellular labeling. Samples were run on a FACSCanto flow cytometer (BD Biosciences) and analyzed using FlowJo software.

Statistics

Statistical analyses were performed using GraphPad Prism software version 7 (GraphPad Software Inc). Data are shown as ±SEM. Bar graphs, tumor growth graphs and survival curves were analyzed using unpaired t-test, 2-way ANOVA, and Log-rank (Mantel-Cox) tests, respectively.

Results

Tumor-specific memory CD8 T cells partially control the growth of B16 melanoma

To confirm that tumor-specific memory CD8 T cells have the capacity to influence the growth of B16 melanoma, mice were infected with L. monocytogenes (LM) or LM expressing ovalbumin (LM-OVA), and at a memory time point immune mice were inoculated with recombinant B16 melanoma expressing ovalbumin (B16-OVA) (Supplemental Fig. 1A). Mice immunized with LM-OVA had reduced tumor burden compared to LM-immunized counterparts, indicating OVA-specific memory CD8 T cells contributed to partial control of tumor growth (Supplemental Fig. 1B-D). To further confirm that tumor-specific memory CD8 T cells control growth of B16 melanoma, mice received adoptive transfer (AT) of memory OT-I CD8 T cells prior to B16-OVA inoculation (Supplemental Fig. 1E). The growth of B16 melanoma was diminished depending on the number of memory OT-I cells transferred prior to B16-OVA implantation (Supplemental Fig. 1F). These data, concomitant with previous reports (16, 17), indicate tumor-specific memory CD8 T cells provide partial control of B16 melanoma.

Pathogen-specific 1°M CD8 TILs do not show measurable Ag-independent effector functions in the tumor

To determine if bystander CD8 TILs perform effector functions in the absence of cognate Ag recognition, mice received 104 Thy disparate naïve OT-I (Thy1.1/1.1) and P14 (Thy1.1/1.2) TCR-Tg cells followed by infection with LM-OVA/GP33 to generate primary memory (1°M) OT-I and P14 cells in the same host. Upon memory establishment (day 30 p.i.) mice were inoculated in the hind flank with B16-OVA cells and 28 days later vasculature-excluded (CD45.2−/i.v.−) and vasculature-derived (CD45.2+/i.v.+) subsets of CD8 T cells from the tumor (Fig. 1A) were analyzed after i.v. injection of fluorescently-conjugated CD45.2 mAb (15, 18). Tumor-specific (OT-I) and pathogen-specific (P14) CD8 T cells were detectable in tumors and majority of cells were bona fide tumor-infiltrating (i.v.−) populations. Comparison of i.v.− and i.v.+ populations revealed expected phenotypic and functional differences (e.g., CD69, IFN-γ, Granzyme B) dependent on the precise localization inside tumor (Fig. 1B). Direct ex vivo analyses (without further manipulations to modify/enhance analyses of CD8 T cell phenotype and function) showed detectable levels of cell activation (CD69), effector cytokine production (IFN-γ), and cytolytic molecules expression (Granzyme B) on i.v.− but not i.v.+ OT-I CD8 TILs further indicating proximity of tumor-specific CD8 T cells to tumor cells and recognition of tumor antigens that potentially contribute to antitumor immunity (Fig. 1C-E). In contrast, pathogen-specific memory CD8 T cells (P14) in the i.v.− subset did not show detectable levels of effector functions in the tumor environment (Fig. 1C-E). Therefore, pathogen-specific 1°M CD8 TILs do not have the measurable capacity to perform Ag-independent functions in response to tumor microenvironment, a notion recently reported by others as well (6).

Figure 1. Pathogen-specific 1°M CD8 TILs do not show measurable Ag-independent effector functions in the tumor.

Figure 1.

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(A) Experimental design. Mice received adoptive transfer of 104 naïve OT-I (Thy1.1+/1.1+) and 104 naïve P14 (Thy1.1+/1. 2+) cells followed by i.v. injection of 1x107 PFU Listeria monocytogenes expressing ovalbumin and glycoprotein 33 (LM-OVA/GP33). After 30 d mice received s.c. injection of 2x104 B16-OVA in the hind flank. After 28 d mice received i.v. injection of fluorescently-conjugated CD45.2 mAb 3 min prior to harvest. (B) OT-I and P14 CD8 T cells were distinguished in tumor samples based on Thy disparity. Cells were divided into vasculature-excluded (CD45.2−/i.v.−) and vasculature-derived (CD45.2+/i.v.+) populations that were phenotypically distinct. Representative histograms of direct ex vivo staining for CD69, IFN-γ and Granzyme B (in the absence of Brefeldin A or monensin (15, 16) on OT-I cells were shown. (C) The frequency of OT-I and P14 CD8 T cells in i.v.+ and i.v.− fractions expressing CD69 (D) IFN-γ and (E) Granzyme B. Data are representative of two independent experiments with 3–5 mice per group per experiment. **=p<0.01; *** = p<0.001 as determined by student t-test, fold change between groups is shown. Error bars are ± SEM.

Pathogen-specific 1°M CD8 T cells do not influence cancer progression

To further confirm that pathogen-specific 1°M CD8 T cells are functionally inert in the tumor microenvironment and do not influence cancer progression, mice received AT of 104 naïve P14 cells followed by LCMV Armstrong 10 or 40 days before B16 implantation to generate mice with high numbers of pathogen-specific primary effector/memory CD8 T cells at the time of B16 inoculation (Fig. 2A). The growth of B16 melanoma in LCMV-immunized hosts was not significantly different compared to naïve non-infected mice (Fig. 2B) As predicted, no correlation was observed between number of pathogen-specific memory CD8 T cells and tumor size/volume (Fig. 2C). Thus, pathogen-specific 1°M CD8 T cells do not perform effector functions in an Ag-independent manner and do not influence the progression of B16 melanoma.

Figure 2. Pathogen-specific 1°M CD8 T cells do not influence cancer progression.

Figure 2.

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(A) Experimental Design. Mice received adoptive transfer of 104 naïve P14 cells followed by i.p. injection of 2x105 CFU LCMV Armstrong 10 or 40 days before s.c. injection of 2x104 B16-OVA in the hind flank. (B) Tumor volume (mm3) at indicated day after B16 injection. (C) Correlation of tumor volume (mm3) 23 days after B16 injection and the frequency of P14 cells in the blood at the time of B16 injection. Data are representative of two independent experiments with at least 5 mice per group. NS=not significant, determined by 2-way ANOVA. Error bars are ± SEM

Since inflammation drives Ag-independent responses of memory CD8 T cells (8), we postulated that 1°M CD8 T cells in the tumor may perform Ag-independent responses in response to high levels of inflammation evoked after a systemic bacterial infection. To test this, LCMV Arm immune, P14 chimera mice, were implanted with B16-OVA and once the tumor was palpable, mice received i.v. injection of virulent LM that does not express GP33 and/or OVA antigens. Ag-independent responses in the spleen and tumor were analyzed 1 day later, an approach we have previously used to analyze bystander CD8 T cells in the spleen (Supplemental Fig. 2A) (12, 19). As expected, splenic memory P14 cells were able to sense virulent LM-induced inflammation and respond in bystander manner (e.g., upregulation of CD69, IFN-γ, and Granzyme B) (Supplemental Fig. 2B-D). However, virulent LM infection was not able to evoke bystander activation and effector cytokine production of i.v.− P14 TILs (Supplemental Fig. 2E-G), potentially due to inability of inflammatory cytokines in circulation to reach CD8 T cells embedded inside a tissue (tumor) (15, 20).

In summary, 1°M CD8 TILs, in the model system used here, are unable to recognize localized tumor-derived or systemic infection-induced inflammation, undergo bystander activation and contribute to antitumor immunity in experimental B16 melanoma model.

Pathogen-specific 4°M CD8 TILs perform Ag-independent effector functions in the tumor and provide measurable antitumor immunity

Our previously published gene expression dataset of memory CD8 T cell populations with different history of antigen encounters showed increased gene expression of inflammatory cytokine receptors (e.g., IL-12 and IL-18) with each sequential infection (10) (Fig. 3A-B). Increased levels of cytokine receptors on multiple stimulated memory CD8 T cells correlated with increased sensitivity to inflammatory cues and ability to undergo bystander activation (12). Thus, we postulated that infection-induced quaternary memory (4°M) CD8 T cells, may have a greater capacity to perform Ag-independent responses in the tumor and influence tumor progression. To test this, mice received AT of Thy disparate naïve and 3°M P14 cells followed by LCMV Arm infection. At the memory time point, mice received s.c. injection of B16-OVA and once the tumor became palpable, 1°M (Thy1.1/1.2) and 4°M (Thy1.1/1.1) P14 cells were differentiated after i.v. labeling with CD45.2 fluorescently-conjugated mAb (Fig. 3C, D). As expected, phenotype of 1°M and 4°M P14 cells in the spleen before tumor inoculation was quite distinct and in accordance to previously published data (Fig. 3E-F) (10). Interestingly, analyses of i.v.− CD8 T cells revealed that 4°M P14 TIL cells had detectable levels of cell activation (CD69), effector cytokine production (IFN-γ), and cytolytic molecules (Granzyme B) compared to 1°M P14 counterparts residing in the same tumor (Fig. 3G-J). Of note: these responses were analyzed directly ex vivo without further in vivo or in vitro stimulation, suggesting that 4°M P14 cells with increased sensitivity to inflammatory cues in the tumor microenvironment might be better suited to provide measurable effector functions and influence tumor progression.

Figure 3. Pathogen-specific 4°M CD8 TILs perform Ag-independent effector functions in the tumor.

Figure 3.

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(A) Experimental design. Mice received adoptive transfer of 104 naïve P14 cells followed by infection with cognate Ag. At a memory time point, 1-5x105 memory P14 cells were adoptively transferred and mice infected to generate higher order memory. (B) The gene expression of IL-12 and IL-18 receptor components in the indicated order of memory CD8 T cells compared to naïve counterparts. (C) Experimental design. Mice received adoptive transfer of 104 naïve P14 (Thy1.1+/1.2+) and 5x105 3°M P14 (Thy1.1+/1.1+) cells followed by i.p. injection of 2x105 CFU LCMV Armstrong. After 22 d mice received s.c. injection of 2x104 B16-OVA in the hind flank. After 9 d mice received i.v. injection of fluorescently-conjugated CD45.2 mAb 3 min prior to harvest. (D) 1°M and 4°M P14 cells (representing 18% and 0.9% of total CD8 T cells, respectively) were distinguished in tumor samples based on Thy disparity. (E) Frequency of KLRG-1 and (F) CD62L expressing P14 cells in the spleen. (G) Representative histograms and gating strategy for indicated marker in i.v.− P14 cells in the tumor. (H) The frequency of 1°M and 4°M P14 cells in i.v.− fraction of tumor samples that express CD69 (I) IFN-γ and (J) Granzyme B. Data are representative of two independent experiments with 4 mice per group. *=p<0.05, **=p<0.01; *** = p<0.001 as determined by student t-test, fold change between groups is shown. Error bars are ± SEM. GEO accession number GSE21360 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21360).

To determine if the bystander responses seen in 4°M P14 cells could improve tumor control and host outcome, separate groups of mice received AT of naïve or 3°M P14 cells followed by LCMV Arm infection. 16 days post LCMV challenge, mice received s.c. injection with B16-OVA and tumor growth was tracked (Fig. 3A). As discussed previously, mice bearing 1°M P14 cells had similar survival and cancer progression compared to naïve counterparts (Fig. 4B-C). In contrast, mice with 4°M P14 cells showed statistically significant improvement in survival and decreased cancer progression (Fig. 4B-C). These data were further corroborated when the frequency of memory P14 cells present at the time of tumor implantation were plotted against tumor size determined 18 days post tumor inoculation (Fig. 4D, E). In addition, TCR stimulation through cognate antigen recognition further enhances effector functions and improves anti-tumor immunity provided by pathogen-specific 4°M P14 cells (Supplemental Fig. 3A-G). Finally, although bystander activation of memory CD8 T cells wanes over time (12), 28 day old 4°M P14 cells were still able to provide measurable anti-tumor immunity in the absence of cognate antigen stimulation (Supplemental Fig. 3H, I).

Figure 4. Pathogen-specific 4°M CD8 T cells influence growth of B16 tumors.

Figure 4.

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(A) Experimental Design. Mice received adoptive transfer of 104 naïve or 5x105 3°M P14 cells followed by i.p. injection of 2x105 CFU LCMV Armstrong 16 days before s.c. injection of 2x104 B16-OVA in the hind flank. (B) Percent survival and (C) Tumor volume (mm3) at indicated day after B16 injection. (D) Correlation of tumor volume (mm3) 18 days after B16 injection and the frequency of 1°M P14 cells at the time of B16 injection. (E) Correlation of tumor volume (mm3) 18 days after B16 injection and the frequency of 4°M P14 cells at the time of B16 injection. Data are representative of two independent experiments with indicated number of mice per group shown. ****= p<0.0001 as determined by 2-way ANOVA, fold change between groups is shown. Error bars are ± SEM.

Thus, these data indicate that memory CD8 T cell populations with heightened sensitivity to inflammatory cues in the environment can contribute to antitumor immunity in Ag-independent manner and that their anti-tumor immunity could be further enhanced by the additional TCR stimulation with cognate antigen.

Discussion

Memory CD8 T cells are recruited to sites of inflammation irrespective of Ag-specificity, resulting in high levels of cancer-unrelated CD8 T cells in the tumor (5-7, 21). A lifetime of CMV and EBV infections could result in a memory CD8 T cell pool consisted of cells with varying history of Ag-encounters that may have capacity to perform bystander responses and contribute to antitumor immunity.

Inflammation is sufficient for bystander 1°M CD8 T cells to become activated and gain effector functions in the context of systemic bacterial infection (Supplemental Fig. 2). However, the B16 environment is potentially less conducive to productive immune responses resulting in low levels of inflammation in the tumor that was not sufficient for bystander 1°M CD8 TILs to perform Ag-independent responses (6). Interestingly, 4°M CD8 T cell responses showed increased sensitivity to inflammation and measurable control of tumor growth in Ag-independent manner.

The capacity of bystander CD8 TILs to respond to inflammation could have important implications for cancer therapy that aims to increase inflammation in the tumor environment such as TLR agonist administration (22). Here, we suggest that the efficacy of therapies designed to turn ‘cold’ tumors ‘hot’ may also elicit Ag-independent responses by tumor-irrelevant memory CD8 T cells, in addition to re-invigorating tumor-specific CD8 T cell responses. Thus, pathogen-specific CD8 T cells may not truly be ‘bystanders’ in the tumors and could present an additional opportunity (or target) to improve CD8 T cell-mediated control of tumor.

Supplementary Material

1

Key Points.

  • Pathogen-specific bystander memory CD8 T cells infiltrate tumors in absence of Ag

  • Primary memory (1°M) bystander CD8 T cells are relatively inert in the tumor

  • 4°M bystander cells gain effector functions independent of cognate Ag recognition

Acknowledgements

Badovinac lab for helpful discussion.

Supported by NIH Grants AI147064, AI114543, GM113961 (V.P.B.), T32AI007485 (D.B.D.), The Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award P30CA086862 (V.P.B).

Footnotes

Conflict of Interest Statement

Authors declare no competing interests

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Supplementary Materials

1
NIHMS1598772-supplement-1.pdf (3.9MB, pdf)

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