Abstract
Immune checkpoint inhibitor-based immunotherapy (ICI) of breast cancer is currently efficacious in a fraction of triple negative breast cancers (TNBC) as these cancers generally carry high tumor mutation burden (TMB) and show increased tumor infiltration by CD8+ T cells. However, most estrogen receptor positive breast cancers (ERBC) have low TMB and/or are infiltrated with immunosuppressive regulatory T cells (Tregs) and thus fail to induce a significant anti-tumor immune response. Our understanding of the immune underpinning of the anti-tumor effects of CDK4/6 inhibitor (CDKi) treatment coupled with new knowledge about the mechanisms of tolerance to self-antigens suggests a way forward, specifically via characterizing and exploiting the repertoire of tumor antigens expressed by metastatic ERBC. These treatment-associated tumor antigens (TATA) may include the conventional tumor neoantigens (TNA) encoded by single nucleotide mutations, TNA encoded by tumor specific aberrant RNA transcription, splicing and DNA replication induced frameshift (FS) events as well as the shared tumor antigens. The latter may include the conventional tumor associated antigens (TAA), cancer-testis antigens (CTA) and antigens encoded by the endogenous retroviral (ERV) like sequences and repetitive DNA sequences induced by ET and CDKi treatment. An approach to identifying these antigens is outlined as this will support the development of a multi-antigen-based immunotherapy strategy for improved targeting of metastatic disease with potential for minimal autoimmune toxicity against normal tissues.
Highlights
ICI has ushered in a revolution in the treatment of cancer, especially of advanced metastatic disease where other treatments have shown limited success [1]
Whereas a fraction of triple negative breast cancers (TNBC) with relatively high mutation load and T cell infiltration are responsive to ICI, most estrogen receptor positive breast cancers (ERBC) have low tumor mutation load that appears inadequate for priming a conventional tumor neoantigens (TNA) targeted CD8+ T cell response with antitumor efficacy
Candidate TNA and tumor associated antigens (TAA) may be predicted from exome sequencing, CAGE-seq, and RNA-seq [29,30,31,32,33] of biopsies from patient’s tumor lesions that progress on ET plus CDK4/6 inhibitor (CDKi) treatment
Summary
ICI has ushered in a revolution in the treatment of cancer, especially of advanced metastatic disease where other treatments have shown limited success [1]. These findings are consistent with other seminal observations that showed that impaired development of Tregs in Foxp mutant mice or depletion of Foxp3+CD25+ Tregs results in widespread multi-organ autoimmunity [49, 50] Together, these studies support the notion that self-tissue antigen or TAA specific T cells with potential for auto-immune pathogenicity/anti-tumor activity are present in the periphery but kept in check by Tregs. The TH1 type immune stimulating tumor microenvironment induced by CDKi treatment and its promotion of increased infiltration of activated T cells into the tumor tissue together could promote increased intratumor T cell expansion and anti-tumor effects [26] These CDKi-mediated effects may not occur in non-dividing normal tissues, which may use an alternative cell cycle signaling pathway involving cyclin E-CDK2 with a prolonged G1 phase [76]. Further increase in the specificity of tumor immunotherapy may occur when targeting multiple TAA such that an individual normal tissue by expressing a limited subset of the TAA may experience further limited autoimmune toxicity
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