Epidemiologic perspectives on immunosuppressed populations and the immunosurveillance and immunocontainment of cancer

Abstract

The advent in the last several years of effective immunotherapy for cancer has renewed interest in the role of the immune system in controlling cancer. The idea that the immune system can help control cancer has a long history. Solid organ transplant recipients (SOTRs) as well as human immunodeficiency virus (HIV)-infected people are affected by cell-mediated immune dysfunction. Epidemiologic studies of these populations reveal a pattern characterized by a strongly increased incidence of virus-related cancers (eg, Kaposi sarcoma, non-Hodgkin lymphoma, and anogenital cancers). In addition, recent epidemiologic studies have evaluated cancer-specific mortality among SOTRs and HIV-infected people following a cancer diagnosis. For a wider range of cancers-not limited to those caused by viruses, and including melanoma and cancers of the colorectum, lung, and breast- these immunosuppressed cancer patients have higher cancer-specific mortality than other cancer patients. This latter group of cancers somewhat mirrors those for which immunotherapy with checkpoint inhibitors is approved. These epidemiologic observations suggest that there are 2 distinct immune selection processes in humans: immunosurveillance directed against premalignant cells before cancer diagnosis (most relevant for preventing virus-related cancers), and "immunocontainment" directed against established cancers. These processes thus appear relevant for different groups of malignancies and may have different mechanisms.

Keywords: cancer/malignancy/neoplasia; cancer/malignancy/neoplasia: registry/incidence; cancer/malignancy/neoplasia: risk factors; clinical research/practice; epidemiology; hematology/oncology; immune deficiency; immunosuppression/immune modulation; translational research/science.

Figure 1.

Standardized incidence ratios (SIRs) for cancer in HIV-infected people and solid organ transplant recipients. SIRs are from sources indicated in the Supplemental Table 1 footnotes. Results for virus-related cancers are shown in red and for virus-unrelated cancers in yellow. Results for cancers for which checkpoint inhibitor therapy has been approved by the US Food and Drug Administration (see Supplemental Table 3) are shown as triangles and for other cancers as circles. The dashed line indicates shows equality in SIRs for the HIV and transplant population. Results are depicted on a logarithmic scale. Abbreviations: BCC basal cell carcinoma, BL Burkitt lymphoma, DLBCL diffuse large B-cell lymphoma, HL Hodgkin lymphoma, KS Kaposi sarcoma, MCC Merkel cell carcinoma, SCC squamous cell carcinoma.

Figure 2.

Hazard ratios for cancer-specific mortality associated with the presence of HIV infection or solid organ transplant. Hazard ratios are from sources indicated in Supplemental Table 2. Results for virus-related cancers are shown in red and for virus-unrelated cancers in yellow. Results for cancers for which checkpoint inhibitor therapy has been approved by the US Food and Drug Administration (see Supplemental Table 3) are shown as triangles and for other cancers as circles. The dashed line indicates shows equality in hazard ratios associated with HIV and transplantation. Abbreviation: DLBCL diffuse large B-cell lymphoma.

Figure 3.

Model for immunosurveillance and immunocontainment of cancer. The blue boxes depict two phases, before vs. at/after diagnosis of cancer, each divided into stages of elimination, equilibrium, and escape, reflecting the engagement of the immune system with premalignant or malignant cells. The red boxes depict examples of important processes that allow immune evasion: expression of immune checkpoint proteins (proposed to affect only the last part of phase 1 but having a much greater effect in phase 2) and immunosuppression associated with solid organ transplantation and HIV infection (affecting phases 1 and 2). Three example scenarios are depicted in the gold boxes and associated text: 1) cancers with virus-related neoantigens under very strong immune selection; 2) cancers with non-viral neoantigens; 3) cancers with both viral and non-viral neoantigens.