Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma

Ficial, Miriam; Jegede, Opeyemi; Sant’Angelo, Miriam; Hou, Yue; Flaifel, Abdallah; Pignon, Jean‐Christophe; Braun, David A.; Wind‐Rotolo, Megan; Sticco-Ivins, Maura; Catalano, Paul J.; Freeman, Gordon J.; Sharpe, Arlene H.; Hodi, F. Stephen; Motzer, Robert J.; Wu, Catherine J.; Atkins, Michael B.; McDermott, David F.; Shukla, Sachet A.; Choueiri, Toni K.; Signoretti, Sabina

doi:10.1158/1078-0432.ccr-20-3084

Cited by 52 publications

(40 citation statements)

References 34 publications

(53 reference statements)

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“…Conversely, absence of these two biomarkers was associated with a 0% response rate. We recently independently validated these findings in RCC in data from Checkmate-025 (31). Thus, our finding of a CD8 + PD-1 + population without TIM-3 or LAG-3 in immunogenic, PD-L1-expressing PCa mirrors findings in the most PD-1-blockade-responsive subset of kidney cancer.…”

Section: Discussionsupporting

confidence: 55%

“…To benchmark our results, we compared them to results obtained with the same multiplex IF panel and same ROI selection in metastatic clear-cell renal cell carcinoma (mRCC) nephrectomy and metastatectomy specimens from the CheckMate-025 trial, a phase III randomized trial comparing nivolumab versus everolimus in patients with RCC previously treated with anti-angiogenic therapy. We recently characterized mRCC immune infiltrates in this trial (31). Median CD8 + density was nearly identical between immunogenic PCa and mRCC (p=1.00, Figure 2C, Supplemental Table 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…Compared with metastatic RCC (mRCC), immunogenic PCa appears to contain a higher density of exhausted progenitors. In Checkmate-025, a trial comparing PD-1 blockade versus everolimus in mRCC, we recently found that density of exhausted progenitors had a significant interaction with treatment arm with respect to progression-free survival (31). Taken together, in immunogenic PCa cases, the findings of exhausted progenitors in APC niches, differentiated effector T cells, and oligoclonal expansion imply an active and tumor-specific immune response.…”

Section: Discussionmentioning

confidence: 99%

“…For multiplex IF panel 2 applied to immunogenic cases and to renal cell carcinoma cases, an in-house six-plex assay was optimized, including antibodies to CD8, PD-1, TIM-3, LAG-3, and TCF1, along with DAPI counterstain ( Supplemental Table 2 ). Details of the image acquisition and image analysis workflow were reported previously (31).…”

Section: Methodsmentioning

confidence: 99%

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A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Calagua

Ficial

Jansen

et al. 2021

Preprint

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PurposeA subset of primary prostate cancer (PCa) expresses programmed death-ligand 1 (PD-L1), but whether they have unique tumor immune microenvironment (TIME) or genomic features is unclear.Experimental DesignWe selected PD-L1-positive high-grade and/or high-risk primary PCa, characterized tumor-infiltrating lymphocytes (TILS) with multiplex immunofluorescence, and identified genomic alterations in immunogenic and non-immunogenic tumor foci.ResultsOne-quarter of aggressive localized PCa cases (29/115) had tumor PD-L1 expression >5%. This correlated with increased density of CD8+ T cells, a large fraction co-expressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM-3 or LAG-3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting-cell niches in close proximity to MHC II+ cells. CD8 T cell density in immunogenic PCa and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent; the latter being strongly associated with a dendritic cell gene set in TCGA. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present.ConclusionsA subset of localized PCa is immunogenic, manifested by PD-L1 expression and CD8+ T cell content comparable to RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by ICIs. Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of localized PCa patients.Statement of Translational RelevanceProstate cancer (PCa) is generally considered poorly immunogenic, with low expression of programmed death-ligand 1 (PD-L1) and low density of tumor-infiltrating immune cells. Accordingly, response rates to PD(L)-1 inhibition in unselected patients with advanced prostate cancer have been low. Here, we find that a substantial subset of aggressive primary PCa exhibits tumor PD-L1 expression and contains a high density of tumor-infiltrating lymphocytes. These lymphocytes contain sub-populations of exhausted progenitor CD8+ T cells and differentiated effector T cells, the hallmarks of ongoing anti-tumor immune response and a prerequisite for response to checkpoint inhibition. Furthermore, we identify genomic alterations that may be contributing to immunogenicity in these cases. These findings point to immune responses elicited in a subset of primary PCa, supporting the development of immune checkpoint blockade clinical trials in early-stage disease, such as biochemically recurrent PCa, that are driven by genomic features of the tumor or the immune microenvironment.

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Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Calagua

Ficial

Jansen

et al. 2021

Preprint

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“…Cancer prevention may be possible via the use of vaccines against HERVs, since HERVs serve crucial roles in early cancer as postulated. There are promising leads that will provide an improved understanding of how HERVs contribute to cancer ( 110 , 139 , 140 ). This knowledge of HERVs will lead to it being used in translational research and will guide researchers to develop vaccines against HERVs preventing cancers.…”

Section: Resultsmentioning

confidence: 99%

Human endogenous retroviruses in cancer: Expression, regulation and function (Review)

Gao

Chen

2020

Oncol Lett

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Human endogenous retroviruses (HERVs) are the remnants of ancient retroviruses that infected human germline cells and became integrated into the human genome millions of years ago. Although most of these sequences are incomplete and silent, several potential pathological roles of HERVs have been observed in numerous diseases, such as multiple sclerosis and rheumatoid arthritis, and especially cancer, including breast cancer and pancreatic carcinoma. The present review investigates the expression signatures and complex regulatory mechanisms of HERVs in cancer. The long terminal repeats-driven transcriptional initiation of HERVs are regulated by transcription factors (such as Sp3) and epigenetic modifications (such as DNA methylation), and are influenced by environmental factors (such as ultraviolet radiation). In addition, this review focuses on the dual opposing effects of HERVs in cancer. HERVs can suppress cancer via immune activation; however, they can also promote cancer. HERV env gene serves a prime role in promoting carcinogenesis in certain malignant tumors, including breast cancer, pancreatic cancer, germ cell tumors, leukemia and Kaposi's sarcoma. Also, HERV ENV proteins can promote cancer via immune suppression. Targeting ENV proteins is a potential future antitumor treatment modality.

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Presence of Tim3⁺ and PD‐1⁺CD8⁺T cells identifies microsatellite stable colorectal carcinomas with immune exhaustion and distinct clinicopathological features

Klapholz

Drage

Srivastava

et al. 2022

The Journal of Pathology

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Colorectal carcinoma (CRC) is the second leading cause of cancer mortality worldwide. CRC is stratified into two major groups: microsatellite stable (MSS) and microsatellite instability-high (MSI-H). MSS CRC constitutes the majority of cases, has worse overall prognosis, and thus far has failed to respond to immunotherapies targeting the immune checkpoint receptors PD-1, PD-L1, and CTLA-4. Here we examined the alternate immunotherapy targets Tim-3 and Lag-3, as well as PD-1, on immune cells in a cohort of MSS CRC using immunohistochemistry and flow cytometry together with mutational analysis and clinical data. We found that PD-1 was variably expressed across CD4 + tumor-infiltrating lymphocyte (TIL) subtypes, and Tim-3 was mostly restricted to CD4 + regulatory T cells. Lag-3, when detected by flow cytometry, was largely coexpressed with Tim-3 and PD-1 in CD4 + TILs. Furthermore, Tim-3 + PD-1 + CD8 + TILs accumulated in the tumor and exhibited a dysfunctional or 'exhausted' phenotype. Notably, we observed a subset of patients with a high proportion of Tim-3 À PD-1 À CD8 + TILs and, conversely, a low proportion of Tim-3 + PD-1 + CD8 + TILs, thus stratifying MSS CRC patients based on a feature of immune exhaustion (MSS-ImmEx). MSS-ImmEx hi patients had abundant Tim-3 + PD-1 + CD8 + TILs, PD-1 + CD4 + effector, and regulatory T cells, and were enriched for left-sided colon tumors and mutations in the APC tumor-suppressor gene. We further investigated the spatial organization of Tim-3, Lag-3, PD-1, and PD-L1 by immunohistochemistry and found higher levels in the tumor margin; however, MSS-ImmEx hi tumors exhibited a higher density of Tim-3 + cells in the tumor center over MSS-ImmEx low tumors. Immunofluorescence revealed a higher density of PD-1 + /CD8 + cells in the tumor center in this group. Our findings identify a subset of MSS CRC that exhibits evidence of higher prior immune activation (MSS-ImmEx hi ) in which therapies targeting Tim-3 in conjunction with anti-PD-1 or other immunotherapies may provide clinical benefit.

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Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma

Cited by 52 publications

References 34 publications

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Human endogenous retroviruses in cancer: Expression, regulation and function (Review)

Presence of Tim3⁺ and PD‐1⁺CD8⁺T cells identifies microsatellite stable colorectal carcinomas with immune exhaustion and distinct clinicopathological features

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Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma

Cited by 52 publications

References 34 publications

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Human endogenous retroviruses in cancer: Expression, regulation and function (Review)

Presence of Tim3+ and PD‐1+CD8+T cells identifies microsatellite stable colorectal carcinomas with immune exhaustion and distinct clinicopathological features

Contact Info

Product

Resources

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Presence of Tim3⁺ and PD‐1⁺CD8⁺T cells identifies microsatellite stable colorectal carcinomas with immune exhaustion and distinct clinicopathological features