Groundbreaking Study Discovers Cancer-Fighting Antibodies in Pancreatic Cancer Patients!

Microsatellite-stable pancreatic ductal adenocarcinoma PDAC have few T cells in cancer cell nests, do not react to immunotherapy, and are thought to only slightly stimulate the innate immune system. Recently, however, it has been discovered that the long-term survival of PDAC patients with tumors that contained tertiary lymphoid structures (TLS) with germinal centers, memory B cells, and memory CD4+ T cells was increased. This finding suggests that anti-PDAC immune responses are present and are clinically relevant and ongoing. A study involving patients with PDAC and colorectal cancer supports the likelihood of these immune responses by showing ongoing anti-tumor immune responses after one week of continuous treatment of an inhibitor to the chemokine receptor, CXCR4.

CT Image of Pancreatic Cancer.

B cell activation will result in B cell clonal growth

These intratumoral immune responses in human PDAC are driven by unknown antigens. The focus has been on T cell clones from PDAC patients with specificity to neoantigens emerging from mutations that predicted cross-reactive microbial epitopes, even though PDAC has a low mutational frequency in comparison to other malignancies. The discovery that immunization of mice with generated pluripotent stem cells gives protection against a number of tumor models lends weight to the idea that the intratumoral immune response may also be directed towards germline-encoded antigens. We may therefore learn more about how PDAC’s immune system interacts with this malignancy if we can identify the variety of antigens that are causing it.

Antigen-membrane immunoglobulin interaction causes B cell activation (Ig). This interaction may result in germinal center responses, antigen presentation to CD4 T cells, and activation of B cells. B cell activation will result in B cell clonal growth, heavy chain (H) isotype switching, H chain and light chain(L) variable region somatic hypermutation (SHM), and eventually differentiation into antibody-secreting plasma cells. As a result, antibodies produced by B cell activation responses may be used to pinpoint the antigens initiating intratumoral immune responses. In the study, scRNA-Seq was employed to identify the paired H and L chains in plasma cells and B cells from primary PDAC tissues, allowing for antibody reactivity screening. The presence of effector CD8 T cells expressing PRF1, GZMB, and IFNG as well as effector CD4 T cells expressing TNF and IFNG was detected using scRNA-Seq sequencing of CD45+ immune cells in primary PDAC samples. PDAC patients exhibit considerably greater titers to F-actin and HSPD1 than a group of healthy donors, according to our examination of plasma titers of F-actin, RUVBL2, and HSPD1.

Clinical significance

Enhancing cancer immunotherapy may be made possible by better understanding the B cell response in PDAC. Whatever the case, the discovery of T cell and B cell responses in PDAC tumors suggests that an adaptive immune response is taking place in the tumor microenvironment, which may be used for tumor control.

Conclusion

PDAC is frequently regarded as one of the more immunologically “silent” carcinomas and is hence immune to cancer immunotherapy. But there is a need for a deeper comprehension of the interaction between this cancer and the immune system, as evidenced by reports of tertiary lymphoid structures in PDAC, neoantigens with homology to peptides derived from infectious diseases in long-term survivors of PDAC, and signs of improved anti-PDAC immunity in metastatic lesions of patients with PDAC after inhibition of CXCR4.