Premed · Premed · Immunology
Lecture 27: Tumor Immunology and Cancer Immunotherapy
Immunology
Learning Objectives
By the end of this lecture, students will be able to:
- Describe the concept of immune surveillance and the evidence for immune control of tumors
- Explain tumor antigens (tumor-specific and tumor-associated) and how they are recognized by the immune system
- Describe the three phases of cancer immunoediting (elimination, equilibrium, escape)
- Explain the major mechanisms of tumor immune evasion
- Describe current cancer immunotherapy approaches including checkpoint inhibitors, CAR-T cells, cancer vaccines, and adoptive cell therapy
Lecture Content
I. Immune Surveillance of Tumors
The cancer immune surveillance hypothesis, proposed by Burnet and Thomas, holds that the immune system continuously monitors for and eliminates nascent tumor cells. Several lines of evidence support this concept. Immunodeficient individuals, including those with HIV/AIDS and organ transplant recipients, have an increased incidence of certain cancers such as Kaposi sarcoma, lymphomas, and skin cancers. Tumor-infiltrating lymphocytes (TILs) correlate with better prognosis in many cancers, including melanoma, colorectal, ovarian, and breast cancer. Spontaneous tumor regression, though rare, has been documented, particularly in melanoma, and is often associated with immune response. Perhaps most compellingly, the success of cancer immunotherapy demonstrates that immune activation can control or eradicate established tumors.
Multiple immune cell types participate in antitumor immunity. CD8+ CTLs are the primary adaptive effectors, recognizing tumor peptides on MHC class I and killing tumor cells. NK cells kill tumor cells that have downregulated MHC class I through missing-self recognition, and also mediate ADCC against antibody-coated tumor cells. CD4+ Th1 cells produce IFN-gamma to activate macrophages and enhance CTL responses. Macrophages in their M1 polarization state are tumoricidal, producing NO, reactive oxygen species, and TNF-alpha, though M2-polarized macrophages are actually pro-tumorigenic. Gamma-delta T cells recognize stress-induced ligands on tumor cells, and dendritic cells cross-present tumor antigens to prime CD8+ T cell responses.
II. Tumor Antigens
Tumor antigens fall into two major categories based on their origin and specificity. Tumor-specific antigens (TSAs), also called neoantigens, arise from somatic mutations unique to the tumor, including point mutations, frameshifts, and gene fusions. These mutated proteins are processed and presented on MHC class I, where they are recognized as foreign by T cells. Neoantigens are highly immunogenic because the immune system has never been tolerized to these novel epitopes. Tumor mutational burden (TMB) correlates with neoantigen load and response to immunotherapy. Examples include mutated KRAS, p53, BRAF, and patient-specific neoantigens.
Tumor-associated antigens (TAAs) are normal self-proteins that are overexpressed, aberrantly expressed, or expressed at the wrong developmental stage. They are less immunogenic because immune tolerance may dampen the response against them. TAAs include several categories. Overexpressed antigens such as HER2/neu in breast cancer and MUC-1. Cancer-testis antigens such as MAGE and NY-ESO-1, which are normally expressed only in the testis (an immune-privileged site) and placenta but become aberrantly expressed in tumors. Differentiation antigens are tissue-specific proteins such as melanocyte antigens (tyrosinase, gp100, MART-1 in melanoma) and PSA in prostate cancer. Oncofetal antigens such as CEA and AFP are expressed during fetal development and re-expressed in cancers.
Viral antigens represent a distinct category found in virus-associated cancers. HPV E6 and E7 proteins in cervical cancer, EBV antigens in Burkitt lymphoma, and HBV/HCV antigens in hepatocellular carcinoma are strongly immunogenic because they are truly foreign proteins.
III. Cancer Immunoediting
The relationship between tumors and the immune system is captured by the concept of cancer immunoediting, which proceeds through three phases known as the "Three Es."
During Elimination, the immune system detects and destroys nascent tumor cells. Innate immunity (NK cells, macrophages, gamma-delta T cells) and adaptive immunity (CTLs) cooperate in this effort. If elimination is complete, the tumor is eradicated, representing immune surveillance in action.
In Equilibrium, the immune system controls but does not fully eliminate the tumor. Tumor cells persist in a dormant state, held in check by immune pressure, and this phase can last years to decades. Critically, during equilibrium, immune selection pressure drives the outgrowth of less immunogenic tumor cell variants through Darwinian selection.
Escape occurs when tumor variants that evade immune recognition grow progressively, and clinically apparent cancer emerges. Multiple evasion mechanisms enable this escape from immune control.
<image>A diagram illustrating the three phases of cancer immunoediting. Phase 1 (Elimination): Normal cells are shown acquiring mutations and transforming into tumor cells (shown with aberrant surface markers/neoantigens). Innate immune cells (NK cells, macrophages) and adaptive immune cells (CD8+ CTLs, CD4+ Th1 cells) attack and destroy the tumor cells. Successful elimination results in no clinical disease. Phase 2 (Equilibrium): Some tumor cell variants survive. The immune system (CTLs, IFN-gamma) keeps the tumor in check (balance scale shown). However, immune pressure selects for tumor cell variants with reduced immunogenicity (shown as cells losing MHC class I expression, gaining PD-L1, or losing neoantigen expression). This phase can last years (indicated by a clock). Phase 3 (Escape): Selected immune-resistant tumor variants proliferate unchecked. The tumor microenvironment is shown: tumor cells expressing PD-L1, secreting TGF-beta and IL-10, recruiting Tregs and myeloid-derived suppressor cells (MDSCs), downregulating MHC I. The tumor grows progressively as a clinically detectable mass. Arrows show the progressive immunoediting from immunogenic to non-immunogenic tumor phenotype.</image>
IV. Mechanisms of Tumor Immune Evasion
Tumors employ multiple strategies to evade immune destruction. Loss of antigen presentation occurs through downregulation or loss of MHC class I molecules (via mutations in beta2-microglobulin, TAP, or HLA genes), loss of tumor antigen expression (antigen-loss variants), and defective antigen processing machinery.
Immune checkpoint exploitation is a key evasion strategy. Tumor cells upregulate PD-L1 (B7-H1), which engages PD-1 on T cells and drives T cell exhaustion and anergy. Tumors may also express other inhibitory ligands such as B7-H3, B7-H4, and VISTA, or exploit the CTLA-4 checkpoint.
The immunosuppressive tumor microenvironment (TME) is actively shaped by tumor cells. They secrete immunosuppressive cytokines including TGF-beta, IL-10, and VEGF. They recruit regulatory T cells (Tregs) that suppress antitumor CTLs, and myeloid-derived suppressor cells (MDSCs) that produce arginase, iNOS, and reactive oxygen species to suppress T cells. Tumor-associated macrophages (TAMs) are predominantly M2-polarized, promoting angiogenesis, suppressing immunity, and facilitating metastasis. IDO (indoleamine 2,3-dioxygenase) expression depletes tryptophan, starving T cells. Metabolic competition further impairs immunity as tumors consume glucose and amino acids, and lactate production creates an acidic microenvironment that causes T cell dysfunction.
Resistance to killing mechanisms include upregulation of anti-apoptotic molecules (Bcl-2, Bcl-xL, survivin), loss of Fas expression or expression of decoy receptors, and expression of serpins that inhibit granzyme B.
V. Cancer Immunotherapy
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Anti-CTLA-4 (ipilimumab) blocks CTLA-4 to enhance T cell priming and activation in lymph nodes, and depletes Tregs in the tumor microenvironment. Anti-PD-1 (nivolumab, pembrolizumab) blocks PD-1 on T cells, preventing PD-L1-mediated exhaustion and reinvigorating tumor-specific CTLs. Anti-PD-L1 (atezolizumab, durvalumab, avelumab) blocks the ligand on tumor cells directly. These agents have shown remarkable efficacy in melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, and many others. Predictive biomarkers for response include PD-L1 expression, tumor mutational burden, microsatellite instability (MSI-high), and TIL density. A significant concern with checkpoint inhibitors is immune-related adverse events (irAEs), autoimmune toxicities including colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis, and dermatitis that arise from unleashed immune responses.
Adoptive cell therapy (ACT) takes several forms. Tumor-infiltrating lymphocyte (TIL) therapy involves harvesting TILs from a patient's tumor, expanding them ex vivo, and infusing them back after lymphodepletion, with particular effectiveness in melanoma. CAR-T cell therapy engineers patient T cells to express a chimeric antigen receptor that recognizes tumor surface antigens directly, independent of MHC. The CAR structure consists of an extracellular scFv (antibody-derived antigen-binding domain), a hinge, a transmembrane domain, and intracellular signaling domains (CD3-zeta plus co-stimulatory domains such as CD28 or 4-1BB). CD19 CAR-T products (tisagenlecleucel, axicabtagene ciloleucel) are FDA-approved for B cell ALL and DLBCL, achieving complete remission rates above 80% in relapsed/refractory B-ALL. BCMA CAR-T is approved for multiple myeloma. Toxicities include cytokine release syndrome (CRS) and neurotoxicity (ICANS). TCR-engineered T cells represent another approach, using T cells engineered with a tumor-specific TCR that, unlike CAR-T, remains MHC-restricted.
Cancer vaccines include both preventive and therapeutic approaches. Preventive vaccines such as the HPV vaccine (preventing cervical cancer) and HBV vaccine (preventing hepatocellular carcinoma) have been remarkably successful. Therapeutic vaccines aim to boost immune responses against existing tumors. Sipuleucel-T for prostate cancer uses autologous dendritic cells loaded with prostatic acid phosphatase. Personalized neoantigen vaccines represent an active area of research, involving tumor sequencing to identify neoantigens, synthesis of corresponding peptides or mRNA, and patient immunization, with mRNA neoantigen vaccines showing particular promise in melanoma.
Monoclonal antibodies directed against tumor antigens exert their effects through multiple mechanisms. Rituximab (anti-CD20) treats B cell lymphomas via ADCC, complement-dependent cytotoxicity, and direct apoptosis. Trastuzumab (anti-HER2) treats breast cancer through ADCC and blockade of HER2 signaling. Cetuximab (anti-EGFR) treats colorectal and head and neck cancers. Antibody-drug conjugates (ADCs) link an antibody to a cytotoxic drug for targeted delivery.
<image>A diagram of CAR-T cell therapy showing the clinical workflow and molecular design. Left panel (Clinical process): Step 1 -- Leukapheresis: T cells are collected from the patient's blood. Step 2 -- Genetic engineering: T cells are transduced with a viral vector encoding the CAR construct. Step 3 -- Expansion: CAR-T cells are expanded ex vivo over 1-2 weeks (shown as multiplying cells in a bioreactor). Step 4 -- Lymphodepletion: the patient receives conditioning chemotherapy. Step 5 -- Infusion: CAR-T cells are infused back into the patient. Step 6 -- Tumor killing: CAR-T cells recognize and kill tumor cells. Right panel (CAR molecular structure): The chimeric antigen receptor is shown spanning the T cell membrane. Extracellular: single-chain variable fragment (scFv) derived from an anti-CD19 antibody, connected by a hinge/spacer region. Transmembrane domain. Intracellular: co-stimulatory domain (CD28 or 4-1BB) connected to CD3-zeta signaling domain. The scFv is shown binding CD19 on a B cell lymphoma cell, triggering T cell activation. Different CAR generations are compared in an inset: 1st gen (CD3-zeta only), 2nd gen (one co-stimulatory domain), 3rd gen (two co-stimulatory domains), 4th gen (armored CARs with cytokine transgene).</image>
