Why this matters: These data reveal a mechanism by which LAG3 inhibits signaling through the TCR independent of its canonical ligand, MHC class II, which may pave the way toward therapeutically targeting the TCR-LAG3 interaction to alleviate T cell inhibition.
“STING-induced regulatory B cells compromise NK function in cancer immunity” by Sirui Li et al
The stimulator of interferon genes (STING) protein is known to induce immune responses via interferon-mediated pathways, however, STING agonists as monotherapy have been unsuccessful as an anti-tumor immunotherapy in clinical studies thus far. In this study, Sirui Li and colleagues report on a novel mechanism of STING agonism resistance induced by regulatory B cells (Bregs). In a pancreatic ductal adenocarcinoma orthotopic mouse model, cGAMP (STING agonist) treatment increased tumor-associated Bregs, including a key population of CD19+IL-35+ Bregs. Increases in B cell-secreted IL-35 resulted in reduced natural killer (NK) cell numbers and cytotoxicity. However, a combination treatment of cGAMP with a neutralizing anti-IL-35 antibody resulted in reduced tumor growth, increased numbers of NK cells, CD8+ T cells, and gene expression changes related to increased proliferation, development, and cytotoxicity in NK cells. Analysis of human B cells derived from peripheral blood mononuclear cells from patients with pancreatic cancer and healthy volunteers confirmed induction of expression of loci encoding IL-35 and IL-10 upon cGAMP treatment, which was enhanced in tumor-bearing patients. In summary, this study reveals a new pathway of interferon resistance mediated by B cell-induced suppression of cytotoxic NK cells.
Why this matters: B cells have been historically overlooked in research and development of cancer immunotherapies. This study highlights the importance of B cells in regulation of cytotoxic responses and validates further research of combination therapies, such as cGAMP with anti-IL-35 agents, to tip the balance towards effective anti-tumor immunity.
“In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue” by Zhi Li et al
J. Exp. Med. (2022
The presence of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) has been associated with improved outcomes with immune checkpoint inhibitors (ICIs) in some solid tumors. While it is understood that TILs in the TME can become phenotypically ‘exhausted’ and activate immunosuppressive pathways, little is known about the temporal and spatial dynamics of different TIL phenotypes in relation to response to ICIs. Zhi Li and colleagues mapped and parsed phenotypic clusters of newly infiltrated immune cells in the TME versus long term residents using a newly developed immune cell photoconvertible mouse xenograft model. The model leveraged Kaede photoconvertible mice, such that a flourochrome expressed by immune cells converts from green to red upon exposure to a 405-nm wavelength light. In established orthotopic MC38 colon tumors, distinct kinetics of infiltration from the periphery and retention in the tumor were seen for CD4+, CD8+, regulatory T cells (Tregs), and natural killer cells. RNA sequencing of the isolated cells that infiltrated the tumor after photoconversion revealed that antigen-specific effector CD8+ T cells became exhausted and gained expression of PD-1, LAG-3, and CD39 within 72 hours. In contrast, non-effector T cells, including TCF-1+ memory and stem-like cells as well as LAG-3-negative Tregs, quickly egressed to draining lymph nodes. Treatment with an anti-PD-L1 ICI resulted in a higher proportion of activated TILs within the tumor, but not increased infiltration from the periphery.
Why this matters: Understanding the mechanisms of immune suppression and exclusion will be essential to future immunotherapy combination approaches. This study offers an innovative new tool to study dynamic changes in tumor-resident and infiltrating T cell phenotypes, which may provide important insights to target these distinct populations.
“Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy” by Adrienne M. Luoma et al
Although neoadjuvant immune checkpoint blockade has demonstrated clinical benefit for patients with squamous cell carcinoma (SCC) of the head and neck, SCC treatment-related immune responses are not fully understood. Adrienne M. Luoma et al performed pre-, on-, and post-treatment single-cell T cell receptor and TCR and RNA sequencing of tumor-infiltrating and circulating T cells isolated from patients with oral cavity SCC who were treated with neoadjuvant nivolumab as monotherapy or in combination with ipilimumab in phase II trial. Among the tumor-infiltrating CD8+ T cell population, the majority of TCR clonotypes that expanded after neoadjuvant treatment pre-existed prior to therapy and expressed markers characteristic of a tissue-resident memory (Trm) phenotype. Screening of TCRs from intratumoral CD8+ T cells from five patients (four of whom had major pathologic response) identified six target antigens for seven TCRs that expanded after treatment, including a previously unidentified HLA C*702-restricted epitope of MAGEA1. In blood, expansion of TCR clonotypes corresponding to the intratumoral populations and expressing activation markers was seen as early as 2 weeks after initiation of therapy. Furthermore, the frequency of pre-treatment CD8+ T cells expressing activation markers (ie, CD38 and HLA-DR) significantly correlated with pathologic response. PD-1 expression alone on peripheral T cells pre- or on-treatment did not predict outcomes to neoadjuvant therapy, however, the percentage of PD-L1 CD8+ T cells that were KLGR1-negative was strongly associated with pathologic response. Altogether, these findings identify key populations of circulating and tumor-infiltrating T cells that expand after neoadjuvant checkpoint blockade, which may inform future biomarker development or combination approaches.
Why this matters: With further validation, peripheral T cell profiling may identify patients likely to benefit with neoadjuvant immunotherapy, and interventions aimed at supporting expansion of tissue resident memory T cells may enhance antitumor responses.
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