Autoimmune Responses in Oncology: Causes and Significance

Abstract

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

Keywords: autoantibodies; autoimmunity; biomarker; cancer immunotherapy; immune-related adverse effects; solid cancers; tumor antigens.

Figure 1

The probable causes of autoimmune responses observed in solid cancers. Various factors ranging from mutations to therapy-induced autoimmunity can lead to autoimmune responses. The multifactorial nature of this phenomenon can contribute to the extent of variation observed in autoimmune responses in patients (PTM: Post-translational modification).

Figure 2

The breaking of immune tolerance in ICI therapy. (A) ICI can lift the inhibitory signal for the activation of self-reactive lymphocytes (left panel) or prevent the apoptosis of effector self-reactive lymphocytes (right panel). (B) Expression of immune checkpoint molecules on healthy cells can lead to the destruction of self-cells by antibody-mediated mechanisms such as activation of the classical complement pathway and antibody-dependent cellular cytotoxicity (ADCC). (C) The effective immune response against the tumor cells as a result of ICI can lead to high amounts of cell death, which results in the release of many self-antigens in a pro-inflammatory milieu. This can enable the activation of self-reactive lymphocytes, which normally have low avidity and affinity to the cognate self-antigen and a high activation threshold.

Figure 3

Advantages of autoantibodies as tumor biomarkers. Autoantibodies can be present at very early stages of disease to help in life-saving early diagnosis of cancer. They are stable molecules which facilitates their detection. Autoantibodies can easily be assayed by conventional and widespread techniques. The parallel detection of multiple autoantibodies is also possible with protein microarrays to increase specificity and sensitivity.