**5. Possible mechanism of action of cytotoxic T lymphocytes (CTLA-4) in cancer**

CTLA-4 (Cytotoxic T lymphocyte-associated protein-4), is another regulatory pathway of T cells. During T cell activation CTLA-4 is highly upregulated. Upon T cell activation, the CTLA-4 is translocated from the intracellular granules to the plasma membrane that further amplifies the T-cell response by regulating T-cell priming and activation. It inhibits the intracellular T cell activation signaling by competitive binding for CD80/CD86 that results in downregulation of immune response. Moreover, it acts through protein tyrosine phosphates 6 and 11 to suppress

#### **Figure 4.**

*Shows CTLA-4 inhibits T cell activation thereby regulating the immune responses. Therefore, tumor cells escape immune response by suppressing CTLA-4.*

the TCR signal. CTLA-4 plays an important role in regulating peripheral tolerance that is an immunological process to prevent auto-immune responses by suppressing T effector cell function and further by upregulating the immunosuppressive Treg activity. Tregs express CTLA-4 constitutively unlike effector cells thereby acting as a major mechanism for immune suppression (**Figure 4**) [14].

Therefore, many monoclonal antibodies are currently being studied for instance; Tremelimumab specific for target CTLA-4 is being investigated in patients with TNBC. Limited research is available regarding CTLA-4, eagerly awaiting the need for research in discovering treatment options and other potential targets in TNBC treatment [31]. By inhibiting the CTLA-4 mediated response or the blockade of CTLA-4 results into the activation of non-specific immune cell activation and is connected with increased treatment-related adverse events (TRAEs). For instance, CTLA-4 depletion has results into rheumatoid arthritis, type I diabetes, collagen induced arthritis and systemic lupus erythematosus [14].
