Peripheral CD8+ T-cell Monitoring for the Prediction of Patient Response to Checkpoint Blockade Therapy Rumya Raghavan1, Ali Rabi Seyed1, Dennie Frederick1, Genevieve Boland1 1Massachusetts General Hospital, Department of Surgery Immune checkpoints (IC) are mechanisms used to establish self-tolerance but are often hijacked by tumors for immune evasion. Immune checkpoint inhibitors (ICI) have seen recent success in the clinic, producing durable responses in a subset of patients with melanoma. However clinicians and researchers have yet to fully characterize mechanisms of de novo and acquired responsiveness to therapy. We have noted a correlation between higher expression of lineage-specific proteins and immunotherapy response, suggesting a breakdown of tolerance to melanocyte lineage specific self-antigens (5). This parallels the clinical observation that vitiligo, a pigmentation disorder resulting from autoimmune destruction of melanocytes, is more prevalent in patients that respond well to immunotherapy (3). Vitiligo has been shown to appear after anti-PD1 therapy in one out of four patients with melanoma and correlates with a better response to therapy (4). This effect is absent from most other types of cancers, implying that there may be epitope spread or some elements of lineage-specific tissue recognition. Based on these findings, we hypothesize that melanocyte lineage-specific antigens are recognized by the immune system during treatment with checkpoint inhibitor blockade in melanoma. We have established an approach to monitor T cell lineage-specific antigen recognition via analysis of peripheral blood-derived T cells during ICI therapy. Several melanocyte-specific antigens are upregulated and highly expressed in melanocytes and melanoma cells (gp100, tyrosinase, MAGEA1, MAGEA3, MART1, etc.) (1,2). Using an MHC dextramer panel with nine melanocyte-specific antigens, we have identified a subpopulation of CD8+ T-cells that are reactive to Tyrosinase and MART1. This subpopulation of CD8+ T-cells increased in frequency following anti-PD1 therapy, suggesting that checkpoint blockade promotes the breakdown of tolerance toward melanocyte-lineage self-antigens. We also noted that in several patients, an increase in lineage-specific antigen positive CD8+ T-cells correlated inversely with RECIST response and was more pronounced in patients with vitiligo. We hypothesize that monitoring of peripheral blood-derived CD8+ T-cell subsets may provide a tool for monitoring lineage-specific cellular recognition during ICI therapy. Moving forward we aim to characterize circulating antigen-specific T cell responses during ICI and undertake comparative analysis with paired tumor infiltrating lymphocytes (TIL) prior to and during ICI therapy.
References: (1) Boyle, Jenny L., et al. “Tyrosinase Expression in Malignant Melanoma, Desmoplastic Melanoma, and Peripheral Nerve Tumors.” Archives of Pathology & Laboratory Medicine, vol. 126, no. 7, July 2002, pp. 816-22. PubMed, doi:10.1043/0003-9985(2002)126<0816:TEIMMD>2.0.CO;2. (2) Fetsch, P. A., et al. “Melanoma-Associated Antigen Recognized by T Cells (MART-1): The Advent of a Preferred Immunocytochemical Antibody for the Diagnosis of Metastatic Malignant Melanoma with Fine-Needle Aspiration.” Cancer, vol. 87, no. 1, Feb. 1999, pp. 37-42. (3) Jacobs, Joannes F. M., et al. “Vaccine-Specific Local T Cell Reactivity in Immunotherapy-Associated Vitiligo in Melanoma Patients.” Cancer Immunology, Immunotherapy, vol. 58, no. 1, Jan. 2009, p. 145. link.springer.com, doi:10.1007/s00262-008-0506-5. (4) Lo, Jennifer. “The Roles of UV, Neoantigens, and Epitope Spreading in Vitiligo and Melanoma.” Grantome. grantome.com, http://grantome.com/grant/NIH/F30-ES025626-01. Accessed 20 Dec. 2017. (5) Sharma, Padmanee, et al. “Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.” Cell, vol. 168, no. 4, Feb. 2017, pp. 707-23. PubMed, doi:10.1016/j.cell.2017.01.017.
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