From Immunogenic Cell Death to Immunogenic Modulation: Select Chemotherapy Regimens Induce a Spectrum of Immune-Enhancing Activities in the Tumor Microenvironment

Abstract

Cancer treatment has rapidly entered the age of immunotherapy, and it is becoming clear that the effective therapy of established tumors necessitates rational multi-combination immunotherapy strategies. But even in the advent of immunotherapy, the clinical role of standard-of-care chemotherapy regimens still remains significant and may be complementary to emerging immunotherapeutic approaches. Depending on dose, schedule, and agent, chemotherapy can induce immunogenic cell death, resulting in the release of tumor antigens to stimulate an immune response, or immunogenic modulation, sensitizing surviving tumor cells to immune cell killing. While these have been previously defined as distinct processes, in this review we examine the published mechanisms supporting both immunogenic cell death and immunogenic modulation and propose they be reclassified as similar effects termed "immunogenic cell stress." Treatment-induced immunogenic cell stress is an important result of cytotoxic chemotherapy and future research should consider immunogenic cell stress as a whole rather than just immunogenic cell death or immunogenic modulation. Cancer treatment strategies should be designed specifically to take advantage of these effects in combination immunotherapy, and novel chemotherapy regimens should be designed and investigated to potentially induce all aspects of immunogenic cell stress.

Keywords: cancer; cell stress; chemotherapy; immunogenic cell death; immunogenic modulation; immunotherapy.

Figure 1

Chemotherapy induces immunogenic cell stress resulting in a spectrum of downstream events from tolerogenic cell death to immune modulation to immunogenic cell death. Tolerogenic cell death induced by chemotherapy is a non-inflammatory cell death that involves the rapid rupture of the plasma membrane and does not trigger immune cells. On the other end of the spectrum, chemotherapy can cause immunogenic cell death that results in the release of DAMPs that promote immune cell phagocytosis, tumor antigen processing, and antigen presentation to T cells. Tumor cells that were not eradicated with chemotherapy undergo immunogenic modulation wherein the tumor surface phenotype is altered to promote T cell targeting of the tumor cell. DAMP, damage-associated molecular patterns; TAA, tumor-associated antigen; MHC, major histocompatibility complex; APM, antigen processing machinery; M6PR, mannose-6-phosphate receptor; NK, natural killer; HMGB1, high mobility group box 1; ATP, adenosine triphosphate; IFN, interferon. Adapted from Ref (14).