Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma Journal Article
| Authors: | Church, C.; Pulliam, T.; Longino, N.; Park, S. Y.; Smythe, K. S.; Makarov, V.; Riaz, N.; Jing, L.; Amezquita, R.; Campbell, J. S.; Gottardo, R.; Pierce, R. H.; Choi, J.; Chan, T. A.; Koelle, D. M.; Nghiem, P. |
| Article Title: | Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma |
| Abstract: | Background: Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (∼80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens. Methods: A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry. Results: WES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγwhen stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet. Conclusions: We identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy. © 2022 Author(s) (or their employer(s)). |
| Keywords: | skin neoplasms; immunotherapy; cd4-positive t-lymphocytes; adaptive immunity; immunity, cellular |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 10 |
| Issue: | 9 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2022-09-01 |
| Start Page: | e005328 |
| Language: | English |
| DOI: | 10.1136/jitc-2022-005328 |
| PROVIDER: | scopus |
| PMCID: | PMC9472219 |
| PUBMED: | 36252564 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2022 -- Source: Scopus |
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