Promotion of an Antitumor Immune Program by a Tumor-specific, Complement-activating Antibody.
Ruchi SaxenaRyan T BusheyMichael J CampaElizabeth B GottlinJian GuoEdward F PatzYou-Wen HePublished in: Journal of immunology (Baltimore, Md. : 1950) (2024)
Tumor-targeting Abs can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with patients with early-stage non-small cell lung cancer. We cloned from their peripheral B cells an mAb, GT103, that specifically recognizes CFH on tumor cells. Although the underlying mechanisms are not well defined, GT103 targets a conformationally distinct CFH epitope that is created when CFH is associated with tumor cells, kills tumor cells in vitro, and has potent antitumor activity in vivo. In the effort to better understand how an Ab targeting a tumor epitope can promote an effective antitumor immune response, we used the syngeneic CMT167 lung tumor C57BL/6 mouse model, and we found that murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances Ag-specific effector T cells, and has an additive antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active tumor microenvironment. More broadly, our results using an mAb cloned from autoantibody-expressing B cells provides novel, to our knowledge, mechanistic insights into how a tumor-specific, complement-activating Ab can generate an immune program to kill tumor cells and inhibit tumor growth.
Keyphrases
- early stage
- regulatory t cells
- immune response
- mouse model
- quality improvement
- healthcare
- monoclonal antibody
- end stage renal disease
- signaling pathway
- dendritic cells
- chronic kidney disease
- ejection fraction
- newly diagnosed
- cancer therapy
- lymph node
- drug delivery
- cell death
- patient reported outcomes
- sentinel lymph node
- cell proliferation
- oxidative stress
- inflammatory response
- papillary thyroid
- highly efficient
- endoplasmic reticulum stress
- patient reported