Methods to Detect Immunogenic Cell Death In Vivo

In response to selected stressors, cancer cells can undergo a form of regulated cell death that-in immunocompetent syngeneic hosts-is capable of eliciting an adaptive immune response specific for dead cell-associated antigens. Thus, such variant of regulated cell death manifests with robust antigenicity and adjuvanticity. As compared to their normal counterparts, malignant cells are highly antigenic per se, implying that they express a variety of antigens that are not covered by central tolerance. However, the precise modality through which cancer cells die in response to stress has a major influence on adjuvanticity. Moreover, the adjuvanticity threshold to productively drive anticancer immune responses is considerably lower in tumor-naïve hosts as compared to their tumor-bearing counterparts, largely reflecting the establishment of peripheral tolerance to malignant lesions in the latter (but not in the former). So far, no cellular biomarker or combination thereof has been found to reliably predict the ability of cancer cell death to initiate antitumor immunity. Thus, although some surrogate biomarkers of adjuvanticity can be used for screening purposes, the occurrence of bona fide immunogenic cell death (ICD) can only be ascertained in vivo. Here, we describe two methods that can be harnessed to straightforwardly determine the immunogenicity of mouse cancer cells succumbing to stress in both tumor-naïve and tumor-bearing hosts.