Abstract 6414: Concomitant anti-tumor immunity and checkpoint blockade responses are restored by depletion of CD62L expressing cells

Abstract

Abstract Studies have shown the importance of CD62L in leukocyte trafficking. However, the significance of CD62L-expressing cells in concomitant anti-tumor immunity has not been investigated. Using a model of post-surgical tumor immunity, we show that in vivo depletion of CD62L-expressing cells before or immediately after surgical tumor resection enabled the development of anti-tumor concomitant responses against poorly immunogenic B16 (melanoma) or MTE-Ras (head & neck cancer) tumor cells. Anti-CD62L mAb administration depleted the cellular immune components that express CD62L, including NK, NKT, Mo, Ma, B, and T cells. Within the T cell compartment, naïve T cells (CD44lo CD62Lhi), effector (CD44hi CD62Llo), memory (CD44hi CD62Lhi) and regulatory T cells (Treg, CD4 CD25 Foxp3) were also depleted, while effector CD62L-negative T cells were spared in the TDLN. Tumor immunity did not occur in the absence of a primary tumor (sham surgery group) or after CD8 depletion. Whereas anti-CTLA-4 or anti-PD-1 mAbs failed as monotherapies, their administration during CD62L depletion restored their anti-tumor properties. The unified global gene expression analysis of the TDLN shows the significant enrichment of biological processes involved in the CD8 T cell effector phase, IL-2/IL-15, TNF-α, IFN-γ, IFN-α, IL-6, responses, mitotic cell division, glycolysis, and acetylation. Also, genes related to Treg responses were downregulated. These data point to a process in which depletion of CD62L cells in tumor-bearing hosts transforms the TDLN into a highly active immunological site in which tumor-reactive effector CD8 T cells (CD62L-negative) actively divide in the absence of Treg, accompanied by a cytokine response, glucose consumption, and acetylation of transcriptional factors and histones. These results identify an unrecognized role of CD62L-expressing cells in regulating concomitant anti-tumor immunity and restoring anti-tumor responses by checkpoint blockade inhibitors. Our study provides a new framework that could help understand how anti-tumor responses are limited. Citation Format: Brianna Burke, Lourdes Plaza-Rojas, Cynthia Perez, Elena Kostenko, Anna Austin, Justin Boucher, Kushal Prajapati, Michael Delos Reyes, Christine Chung, Jose-Alejandro Guevara-Patino. Concomitant anti-tumor immunity and checkpoint blockade responses are restored by depletion of CD62L expressing cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6414.