Questions: Tumor Immune Surveillance and Immunoediting

Question 1

A clinically detected tumor has very low MHC class I expression and high PD-L1 expression. Rather than being a random tumor property, immunoediting theory predicts this most likely occurred because:

• A. The tumor arose in an immunodeficient patient who lacked the immune pressure necessary to select for any specific phenotype
• B. Darwinian selection under immune pressure favored clones with these immune-evasive features — low MHC hides cells from CTLs, high PD-L1 exhausts attacking T cells
• C. MHC downregulation and PD-L1 upregulation are early driver mutations that cause malignant transformation
• D. These features reflect normal tissue-specific gene expression rather than immune selection

Answer: (B)

Immunoediting posits that immune pressure acts as a selective force on genetically unstable tumor populations. Clones that happen to downregulate MHC class I (becoming invisible to CTLs, which require MHC-peptide recognition) or overexpress PD-L1 (which engages PD-1 on T cells, triggering exhaustion) survive immune attack better than immunogenic clones. Over years of immune selection, these evasive phenotypes dominate the tumor population. This is Darwinian selection operating within the tumor microenvironment, not a fixed tumor-intrinsic property.

Question 2

Checkpoint inhibitors like anti-PD-1 antibodies work primarily by:

• A. Stimulating dendritic cells to create new tumor-specific T cell responses from naive T cells
• B. Directly killing tumor cells by binding to PD-L1 and triggering complement activation
• C. Blocking the inhibitory signal that exhausted tumor-infiltrating T cells receive, unleashing pre-existing immune responses the tumor had suppressed
• D. Preventing new tumor mutations by stabilizing DNA repair pathways in cancer cells

Answer: (C)

Checkpoint inhibitors do not generate new immune responses. Tumor-infiltrating lymphocytes (TILs) are often already present but functionally exhausted — their effector functions suppressed by continuous PD-L1/PD-1 signaling, TGF-β, and other immunosuppressive factors. Anti-PD-1 antibodies block the PD-1 receptor on T cells, preventing PD-L1 from delivering the inhibitory signal. This reverses suppression of tumor-reactive T cells already recruited to the tumor. The success of checkpoint blockade is therefore contingent on pre-existing tumor-infiltrating T cells.

Question 3

Tumors escape immune surveillance mainly by becoming invisible — they simply stop expressing surface proteins that the immune system could recognize.

• T. True
• F. False

Answer: False

While MHC downregulation (hiding cells from CTL recognition) is one immune evasion strategy, tumors also actively suppress immunity rather than merely hiding. They recruit regulatory T cells (Tregs) that suppress effector T cells, polarize macrophages toward immunosuppressive phenotypes, secrete TGF-β and IL-10 that dampen immune responses, and create physical immune exclusion zones. Many tumor-infiltrating lymphocytes are present but exhausted or anergic — dysfunctional, not simply absent. Active suppression is as important as invisibility for immune evasion.

Question 4

Clinically detected cancers are often poorly immunogenic because years of immune pressure selected for the least immunogenic clones in the tumor population.

• T. True
• F. False

Answer: True

This is the central insight of immunoediting. Tumor cells that eventually cause clinical disease are not a random sample of all transformed cells — they are survivors of immune selection. Highly immunogenic clones were eliminated during the elimination and equilibrium phases. What remains is enriched for clones that evaded immunity, which are by definition less immunogenic. This selection bias explains why late-stage tumors often respond poorly to immunotherapies that would have worked well on the original, more immunogenic tumor population.

Question 5

Explain why checkpoint inhibitors (anti-PD-1, anti-CTLA-4 antibodies) depend on pre-existing tumor-reactive T cells to work, rather than creating immunity from scratch.

Model answer: Checkpoint inhibitors work by removing inhibitory signals from T cells that have already been recruited to the tumor microenvironment but are functionally suppressed. PD-1 on T cells is engaged by PD-L1 on tumor cells, delivering an exhaustion signal; anti-PD-1 blocks this interaction, allowing those T cells to re-engage their cytotoxic functions. If no tumor-reactive T cells are present in the tumor ('cold' or immune-excluded tumors), there is nothing for checkpoint blockade to unleash. Creating a de novo T cell response requires antigen presentation, priming in lymph nodes, and clonal expansion — processes that checkpoint inhibitors don't directly address.

This is why 'cold tumors' — those without tumor-infiltrating lymphocytes — often fail to respond to checkpoint immunotherapy. Combination strategies try to 'heat up' cold tumors (using vaccines, oncolytic viruses, or radiation to increase antigen release and T cell recruitment) before applying checkpoint blockade. Understanding that checkpoint inhibitors reverse suppression rather than induce new responses is essential for predicting which patients will respond and for designing rational combination approaches.