Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing

Sofia R Gameiro,James W Hodge,Soldano Ferrone,Momodou L Jammeh,Kwong Y Tsang,Max M Wattenberg

doi:10.18632/oncotarget.1719

Sofia R Gameiro, James W Hodge + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.1719

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Abstract

Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response. This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone.

Highlights

Radiation therapy (RT) is standard of care for multiple malignancies, including carcinomas of the breast, lung, and prostate
Radiation induces dose-dependent alterations in human carcinoma cells ranging from immunogenic modulation to cardinal signs of immunogenic cell death
Studies in preclinical models have shown that radiationinduced tumor-cell death is immunogenic and elicits strong antitumor immunity, a process described by Zitvogel and Kroemer et al as immunogenic cell death (ICD) [1,2,3]

Summary

Introduction

Radiation therapy (RT) is standard of care for multiple malignancies, including carcinomas of the breast, lung, and prostate. Preclinical studies in various tumor models have shown that exposing tumor cells to lethal doses of radiation can elicit cell death while inducing strong antitumor immunity in a process initially described by Zitvogel and Kroemer et al as immunogenic cell death (ICD) [1,2,3]. We demonstrated in both preclinical and clinical studies that radiation combined with vaccine elicits greater tumor antigen-specific CD8+ T-cell responses and/or reduction in tumor burden than either modality alone [10, 11]. We examined radiation’s ability to induce immunogenic modulation (IM) of breast cancer, non-small cell lung cancer (NSCLC), and prostate cancer cells, increasing their susceptibility to CD8+ CTL-mediated lysis. T cell-mediated killing relies on the recognition of specific CD8+-restricted epitopes associated with MHC class I molecules on the surface of tumor cells, which is dictated by the cooperative action of multiple elements of the antigen-processing machinery (APM). We examined the effects of radiation on molecules that have been implicated in enhancing CTL-

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