Antigenic profiles of individual-matched pairs of primary and melanoma metastases

Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses

“…Thus, it is not surprising that cancer cells within an established tumor are able to resist anti‐tumor immunity. Beyond the indirect contribution of the hypoxic as well as immunosuppressive microenvironment within a growing tumor, cancer cells directly employ a number of mechanisms for immunoevasion; these include, but are not limited to, the following—(i) acquaintance of low immunogenicity, by downregulating tumor‐associated antigens (TAAs) and major histocompatibility complex (MHC) class I expression; (ii) inciting tolerance by suppressing CD4 + /CD8 + T cells via immunosuppressive cytokines (like interleukin‐10 or IL10 and transforming growth factor β or TGFβ), factors suppressing lymphocyte chemotaxis or immune‐checkpoints (like programmed cell death 1 or PD1, programmed cell death‐ligand 1 or PD‐L1, cytotoxic T lymphocyte‐associated protein‐4 or CTLA4) thereby facilitating differentiation of immunosuppressive regulatory T cells (CD4 + CD25 + FoxP3 + Tregs); (iii) taking advantage of T cells’ low affinity toward TAAs‐MHC complexes which reduces their long‐term persistence as memory T cells; and last but not least, (iv) resisting immune cell‐mediated lysis by blunting extrinsic/intrinsic cell death pathways …”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[105][106][107][108][109][110] Accordingly, RCD can no longer be perceived as immunogenic when: (1) the intracellular stress responses regulating the emission of ICD-associated DAMPs are pharmacologically or genetically ablated in cancer cells; or (2) when the molecular machinery dedicated to DAMP detection is inhibited or ablated. 13,44,84,91,93,97 Moreover, ICD-driven immunity can no longer operate in the presence of general immunological defects, 111 such as (1) an intrinsically low antigenicity of cancer cells, owing to low levels of TAAs or downregulation of MHC Class I molecules [112][113][114][115][116][117][118][119] ; (2) an increased immunological tolerance of the host, secondary to increased amounts of immunosuppressive cytokines, [120][121][122][123][124][125][126][127][128] or inhibitors of chemotaxis, [129][130][131][132][133][134] increased tumor infiltration by immunosuppressive cell populations, [135][136][137][138][139][140]…”

Cancer immunogenicity, danger signals, and DAMPs: What, when, and how?

“…Cancer immunoediting process usually leads to formation of cancer cells that have been “immunoedited” to resist anti‐tumor immunity . Their resistance tactics include: Acquaintance of low immunogenicity: ability to incite tolerance by activating regulatory T cells (CD25 + FoxP3 + Tregs that can secrete immunosuppressive factors) on account of self‐antigen overexpression , ability to vary antigen profile , ability to shed tumor antigens so as to block tumor‐specific antibodies and T‐cell receptors, loss of MHC class I molecule expression , taking advantage of general T cells' low affinity toward MHC‐peptide complexes based on the tumor‐associated antigens (TAAs) and de‐regulation of antigen processing and presentation pathways ; Ability to induce immunotolerance or active immunosuppression: through immunosuppressive cytokines like IL‐10 or transforming growth factor‐beta (TGF‐β) ; or expression of immune cell checkpoint ligands that inhibit anti‐tumor immunity ; Ability to resist immune cell‐mediated lysis: by secreting or expressing “TNF‐related apoptosis‐inducing ligand/TRAIL” decoy receptors, caspase‐inhibiting proteins, granzyme B‐inhibiting proteins or by down‐regulating/mutating death receptors and caspase‐8 . …”

“…It is worth mentioning that cancer immunogenicity, apart from the above‐mentioned predominantly cell‐extrinsic general tactics, can also be profoundly influenced by individual tumor properties like tumor tissue/type and cell‐autonomous features like cancer cell's genetic or epigenetic background. For instance, while all types of tumors carry TAAs and exhibit a certain amount of MHC class I expression yet different tumor types (or even different stages of the same tumor type) may differ in their overall expression of TAAs and MHC class I molecules thereby displaying varying degree of immunogenicity . Such differences may arise from genetic or epigenetic processes unique to the cancer cells of the tumor under consideration for example, expression of particular TAAs due to demethylation , hypomethylation, or histone acetylation of encoding genes (like in the case of various cancer testis antigens) ; creation of more “antigenic mutations” or “neo‐antigens” owing to impairment of DNA mismatch repair , mutations in oncogenes (like KRAS ), or chromosomal rearrangement (like in the case of BCR ‐ ABL1 ) ; epigenetic regulation of MHC class I levels ; and last but not least, their hyperploid chromosomal content which is associated with a constitutive ER stress response that ultimately contributes to cancer immunosurvelliance .…”