A 68-year-old man comes to the office for a follow-up appointment. He has a history of advanced melanoma that is unresectable and resistant to adjuvant regimens. The patient recently began receiving monoclonal antibody infusions for advanced melanoma. The monoclonal antibodies block a specific cell surface receptor found on T lymphocytes. As a result, T cells capable of recognizing tumor antigens have improved ability to destroy cancer cells. Which of the following cell surface receptors is most likely blocked by the treatment?

Question

A 68-year-old man comes to the office for a follow-up appointment.  He has a history of advanced melanoma that is unresectable and resistant to adjuvant regimens.  The patient recently began receiving monoclonal antibody infusions for advanced melanoma.  The monoclonal antibodies block a specific cell surface receptor found on T lymphocytes.  As a result, T cells capable of recognizing tumor antigens have improved ability to destroy cancer cells.  Which of the following cell surface receptors is most likely blocked by the treatment?

Quizplus · Accepted Answer

11ec160b_37b3_e37e_9249_4990dd71e3ad_MD0001_00 Oncogenesis generates proteins not found in healthy cells. Pieces of these proteins (neoantigens) are displayed on the cell surface and may be recognized by cytotoxic T-cells as "non-self" (leading to cellular apoptosis). However, neoplastic cells can blunt the cytotoxic T-cell response through a variety of mechanisms including the overexpression of programmed death-ligand 1 (PD-L1), which binds to the PD-1 receptor on cytotoxic T cells and inhibits their ability to induce apoptosis (T-cell exhaustion). Treatment with monoclonal antibodies against PD-1 (eg, pembrolizumab, nivolumab) or PD-L1 (eg, atezolizumab) results in T-cell disinhibition and a restoration of the cytotoxic response (thereby increasing cancer cell apoptosis). Anti-PD-1 therapy is currently used in advanced melanoma, certain types of lung cancer, and renal cell carcinoma but is being explored for many other cancer types. (Choices A and B) HIV uses chemokine coreceptor 5 (CCR5) to bind to CD4 cells. Antagonists to CCR5 have been developed for the management of patients with HIV. CCR5 also appears to promote CD4 cell anti-tumor responses, so antibodies blocking its function may downregulate immune-mediated tumor destruction. Blockade of CD4 itself would inhibit helper T-cell activation and reduce tumor cell destruction. (Choice C) CD19 is expressed primarily on B cells (not T cells) and is important for B-cell signaling and activation. (Choice D) CD28 is a T cell-specific surface protein that interacts with B7 on antigen-presenting cells, providing a costimulatory signal necessary for T-cell activation. Therefore, antibodies blocking CD28 would inhibit T-cell activation. CTLA-4 also binds to B7 but has an inhibitory function on activated T cells. Educational objective: The binding of programmed cell death protein 1 (PD-1) to one of its ligands (programmed death-ligand 1 [PD-L1]) downregulates the immune response by inhibiting cytotoxic T cells. Many types of cancers evade immunodetection by increasing expression of PD-L1 on their surface. Monoclonal antibodies against PD-1 upregulate the T-cell response and promote tumor cell apoptosis. __________ References: Evolving concepts: immunity in oncology from targets to treatments. (http://www.ncbi.nlm.nih.gov/pubmed/26060497) The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. (http://www.ncbi.nlm.nih.gov/pubmed/25823918) The B7 family and cancer therapy: costimulation and coinhibition. (http://www.ncbi.nlm.nih.gov/pubmed/17875755) Cytotoxic T-lymphocyte-associated antigen-4. (http://www.ncbi.nlm.nih.gov/pubmed/21467163) Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity. (http://www.ncbi.nlm.nih.gov/pubmed/23281743) CCR5 in cancer immunotherapy: more than an "attractive" receptor for T cells. (http://www.ncbi.nlm.nih.gov/pubmed/22720226)

A 68-Year-Old Man Comes to the Office for a Follow-Up