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Published on: October 30, 2013
Guanylyl cyclase C-induced immunotherapeutic responses opposing tumor metastases without autoimmunity
Adam E Snook1, Benjamin J Stafford, Peng Li
1Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South Tenth St, Philadelphia, PA 19107, USA.
Background:
One of the greatest impediments to cancer immunotherapy is the paucity of antigens that are tumor specific, sufficiently immunogenic, and shared among patients. Mucosa-restricted antigens that are expressed by tumor cells represent a novel class of vaccine targets that are characterized by immunologic privilege, which limits systemic tolerance to those antigens, and immunologic partitioning, which shields mucosae from systemic autoimmune responses. Here we defined the immunogenicity and antitumor efficacy of guanylyl cyclase C (GCC), a protein that is normally restricted to intestinal mucosa and universally expressed by metastatic colorectal cancer.
Methods:
BALB/c mice (n = 197) were immunized with recombinant GCC-expressing viral vectors before (prophylactic) or after (therapeutic) a lethal challenge of GCC-expressing mouse colon cancer cells, and antitumor efficacy was monitored by quantifying metastasis and survival. Induction of autoimmunity was monitored by histopathology. Induction of GCC-specific B-cell and CD4(+) and CD8(+) T-cell responses were determined by enzyme-linked immunosorbent assay and ELISpot, respectively. Tolerance to GCC was quantified by comparing responses in GCC-deficient (n = 45) and wild-type (n = 69) C57BL/6 mice. Statistical tests were two-sided.
Results:
Immunization with GCC-expressing viral vectors reduced the formation of metastases to liver (control vs GCC: mean = 30.4 vs 3.55 nodules, difference = 26.9 nodules, 95% confidence interval [CI] = 8.47 to 45.3 nodules; P = .008) and lung (control vs GCC: mean = 263 vs 55.7 nodules, difference = 207, 95% CI = 163 to 251; P < .001) and extended the median survival of mice with established lung metastases following therapeutic immunization (control vs GCC: 29 vs 38 days, P = .024), without autoimmunity. Antitumor efficacy reflected asymmetrical tolerance that was characterized by CD8(+) T-cell, but not CD4(+) T-cell or antibody, responses.
Conclusions:
Immunologic partitioning together with immunologic privilege highlight the potential of mucosa-restricted antigens, particularly GCC, as therapeutic targets for metastatic cancer.
Insights
Targeting guanylyl cyclase C (GCC), a tumor-specific antigen, with viral vectors significantly reduced metastasis and improved survival in preclinical models of colorectal cancer. This approach shows promise for cancer immunotherapy without inducing autoimmunity.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Cancer immunotherapy faces challenges due to a lack of tumor-specific, immunogenic, and shared antigens.
- Mucosa-restricted antigens, like guanylyl cyclase C (GCC), offer novel vaccine targets due to immunologic privilege and partitioning, limiting systemic tolerance and autoimmune responses.
- GCC is expressed in intestinal mucosa and universally in metastatic colorectal cancer, making it a potential therapeutic target.
Purpose of the Study:
- To define the immunogenicity and antitumor efficacy of guanylyl cyclase C (GCC) as a vaccine target for metastatic colorectal cancer.
- To evaluate the potential of GCC-based immunotherapy in reducing tumor burden and improving survival.
- To assess the induction of autoimmunity and the nature of immune responses generated against GCC.
Main Methods:
- BALB/c mice were immunized with GCC-expressing viral vectors, either prophylactically or therapeutically, against a GCC-expressing colon cancer cell challenge.
- Antitumor efficacy was assessed by quantifying liver and lung metastases and monitoring survival.
- Immune responses, including GCC-specific B-cell, CD4(+), and CD8(+) T-cell responses, and autoimmunity were evaluated.
Main Results:
- GCC-based immunization significantly reduced liver and lung metastases compared to controls.
- Therapeutic immunization with GCC extended the median survival of mice with established lung metastases.
- The observed antitumor efficacy was associated with CD8(+) T-cell responses, without inducing autoimmunity.
Conclusions:
- Mucosa-restricted antigens, exemplified by GCC, hold significant potential as therapeutic targets for metastatic cancer.
- The mechanisms of immunologic partitioning and privilege contribute to the efficacy of GCC-based immunotherapy.
- GCC-targeting vaccines represent a promising strategy for overcoming challenges in cancer immunotherapy.
