Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Functional T Cell Reactivity to Melanocyte Antigens is Lost During Development of Malignant Melanoma, but is Restored with Successful Immunotherapy

Version 1 : Received: 5 December 2020 / Approved: 7 December 2020 / Online: 7 December 2020 (13:53:31 CET)

How to cite: Lehmann, P. Functional T Cell Reactivity to Melanocyte Antigens is Lost During Development of Malignant Melanoma, but is Restored with Successful Immunotherapy. Preprints 2020, 2020120160 (doi: 10.20944/preprints202012.0160.v1). Lehmann, P. Functional T Cell Reactivity to Melanocyte Antigens is Lost During Development of Malignant Melanoma, but is Restored with Successful Immunotherapy. Preprints 2020, 2020120160 (doi: 10.20944/preprints202012.0160.v1).

Abstract

Healthy human subjects develop spontaneous CD8+ T cell responses to melanocyte antigens (MA) expressed by normal melanocytes, such as Tyrosinase, MAGE-A3, Melan/Mart-1, gp100, and NY-ESO-1. This natural autoimmunity directed against melanocytes might confer protection against the development of malignant melanoma (MM), where MA are present as overexpressed tumor-associated antigens. Consistent with this notion we report here that functional T cell reactivity to MA was found to be diminished in untreated MM patients: while 57.5% of healthy controls (n=40) exhibited high-frequency MA-specific T cell reactivity ex vivo, such was detected in only 12% of the untreated MM patients (n=24). Three lines of evidence suggest that the MA-reactive T cells present in healthy subjects undergo exhaustion once MM establishes itself. First, only the MA-specific T cell reactivity was affected in the MM patients; that to third party recall antigens was not. Second, in these patients, the residual MA-specific T cells, unlike third party antigen reactive T cells, were functionally impaired, showing a diminished per cell IFN-γ productivity. Third, successful immunotherapy with AGI-101H melanoma vaccine restored natural CD8+ T cell autoimmunity to MA in 85% of the vaccinated patients (n= 27). The role of natural T cell autoimmunity to tumor-associated MA is discussed based on discrete levels of T cell activation thresholds.

Subject Areas

melanoma; genetic whole cell therapeutic melanoma vaccine (AGI-101H); CD8+ T cells; melanoma antigens; ELISPOT

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