Antibodies that block checkpoint receptors, such as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), have shown remarkable clinical effects. However, durable responses to checkpoint blockers have been obtained in only a fraction of patients , suggesting that persistence of immunosuppressive mechanisms may contribute to intrinsic resistance to cancer immunotherapy.
Cells in the tumor microenvironment attributed with immunosuppressive activities include cancer-associated fibroblasts, myeloid-derived suppressor cells, and CD4+ regulatory T (Treg) cells expressing the transcription factor FOXP3. Specifically, Treg cells play an essential role in suppressing aberrant immune responses against self-antigens and anti-tumor immune responses. Treg cells are potent suppressors of effector T cells, and, consequently, increased densities of tumor-infiltrating Treg cells have been associated with poor prognosis in a number of cancers
Treg cells can suppress effector T cells through different direct mechanisms, including secretion of inhibitory cytokines, granzyme-mediated cytolysis of effector T cells, and metabolic impairment of effector T cells—for example, by depletion of interleukin-12 (IL-12)—as well as indirect mechanisms such as suppression of dendritic cell maturation and function
RNA-sequencing analysis revealed marked transcriptomic differences between tumor- or tissue-resident Treg versus peripheral blood Treg cells, whileTumors with more aggressive phenotypes, such as triple-negative breast cancers (TNBCs), contained higher frequencies of Treg cells, which might imply an active role for Treg cells in cancer progression
CCR8 es un buen candidato para inhibir la respuesta inmunosupresiva. Sin embargo se expresa en el corazón e hígado, por lo que podrían darse problemas autoinmunes.the gene expression profiles were highly comparable between Treg cells present in breast tumor and normal tissue
marked expression of chemokine receptor 8 (CCR8), a molecule implicated in the modulation of immunogenicity in colorectal cancer (CRC) , was identified as a unique feature of intratumoral Treg cells
Interesantemente los tumores que expresan mayor regulación al alza de respuesta inmunosupresora CTLA4, LAG3, TIM3 correlacionan con peor 5 YR survival.authors found a strong negative association between the ratio of CCR8/FOXP3-expressing cells and patient survival
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