Abstract A13: Neoadjuvant PD-1 mAb treatment induces postoperative immune memory responses against both immunodominant and immunorecessive antigens
Authors: Allen Clint T. , Friedman Jay , Zolkind Paul , Uppaluri Ravindra 
Published: September 2020

Induction of T-cell responses to immunorecessive tumor antigens may be important for generation of polyclonal responses capable of eliminating immunoedited tumor cells that have lost immunodominant antigens. We hypothesized that neoadjuvant PD-1 mAb immune checkpoint inhibition (ICI) before surgery could induce polyclonal T-cell responses and lead to immunologic memory capable of preventing engraftment upon challenge with tumor cells lacking immunodominant antigen. Antigen immunodominance was established in two models of oral cancer using ELISpot and cytotoxicity assays with tumor-infiltrating lymphocytes (TIL) cultured from tumors. Mice bearing tumors harboring both immunodominant and immunorecessive antigens were treated with PD-1 or isotype control mAb before surgical extirpation. Forty days after surgery, mice were challenged with tumor cells harboring immunorecessive antigens with or without immunodominant antigens. Following neoadjuvant treatment with control mAb, mice readily engrafted progressing tumors upon challenge with tumor cells lacking immunodominant antigens. Following neoadjuvant treatment with PD-1 mA, mice failed to engraft tumors upon challenge with tumor cells lacking immunodominant antigens. TIL cultured from tumors following treatment with PD-1 mAb killed tumor cells lacking immunodominant antigens, whereas TIL cultured from tumors treated with control mAb did not. T cells harvested from tumor-draining lymph nodes (TDLN) 40 days after resection were assessed for antigen-specific interferon (IFN) production. Mice treated with neoadjuvant PD-1 mAb displayed antigen-specific responses against both immunodominant and immunorecessive antigens, whereas mice treated with control mAb did not. Further, mice treated with neoadjuvant PD-1 mAb developed immunodominant and immunorecessive tetramer-positive CD44+CD62L- effector memory T cells in the periphery, whereas mice treated with control mAb did not. Taken together, these data suggest that neoadjuvant PD-1 mAb is capable of inducing antigen-specific T-cell responses against both immunodominant and immunorecessive antigens. This effector response before surgery leads to the development of antigen-specific memory that is capable of resisting challenge with tumor cells that have lost the immunodominant antigen. This work provides a mechanism previously not described for PD-1 mAb treatment and strongly supports the use of PD-blocking ICIs in the neoadjuvant setting before surgery for head and neck cancer.

Citation Format: Clint T. Allen, Jay Friedman, Paul Zolkind, Ravindra Uppaluri. Neoadjuvant PD-1 mAb treatment induces postoperative immune memory responses against both immunodominant and immunorecessive antigens [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A13.