Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer.

Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI-chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [18F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (TEM) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [18F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing TEM cells responsible for durable immunological memory response to combination therapy in vivo.

Examining Immunotherapy Response Using Multiple Radiotracers.

PURPOSE: Cancer immunotherapy has shown huge potential in the fight against cancer, but only a small proportion of patients respond successfully to treatment. Non-invasive methods to stratify responders from non-responders are critically important as immune therapies are often associated with immune-related side effects. Currently, conventional clinical imaging modalities do not provide a useful measure of immune therapy efficacy. Sensitive imaging biomarkers that provide information about the tumoural microenvironment may provide useful insights allowing for improved patient management. PROCEDURES: We have assessed the ability of a number of radiopharmaceuticals to non-invasively measure different aspects of the tumour microenvironment and correlated tumour uptake to immune therapy response in a syngeneic model of colon cancer, CT26-WT. Four radiopharmaceuticals, [18F]FDG (a glucose analogue), [18F]FEPPA (a marker for macrophage activation), [18F]FB-IL2 (a marker for CD25+ cells) and [68Ga] Ga-mNOTA-GZP (a marker for granzyme B, the serine protease downstream effector of cytotoxic T cells), were assessed as potential biomarkers to help stratify response to PD-1 monotherapy or combined anti-PD1 and CLTA4 therapy in vivo correlating tumour uptake with changes in tumour-associated immune cell populations. RESULTS: [18F]FDG, [18F]FEPPA and [18F]FB-IL2 (a marker for CD25+ cells) showed limited ability to determine therapy response and showed little correlation to tumour-associated immune cell changes. However, [68Ga] Ga-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells. CONCLUSIONS: [68Ga]Ga-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations supporting continued development of granzyme B-based imaging agents for stratification of response to immunotherapy. Early assessment of immunotherapy efficacy with [68Ga]Ga-mNOTA-GZP may allow for the reduction of unnecessary side effects while significantly improving patient management.

TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells.

The molecular checkpoints that drive inflammatory bowel diseases are incompletely understood. Here we found more T cells expressing the transcription factor PU.1 and interleukin 9 (IL-9) in patients with ulcerative colitis. In an animal model, citrine reporter mice had more IL-9-expressing mucosal T cells in experimental oxazolone-induced colitis. IL-9 deficiency suppressed acute and chronic colitis. Mice with PU.1 deficiency in T cells were protected from colitis, whereas treatment with antibody to IL-9 suppressed colitis. Functionally, IL-9 impaired intestinal barrier function and prevented mucosal wound healing in vivo. Thus, our findings suggest that the TH9 subset of helper T cells serves an important role in driving ulcerative colitis by regulating intestinal epithelial cells and that TH9 cells represent a likely target for the treatment of chronic intestinal inflammation.