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Immunotherapy has only had a modest impact on the treatment of advanced GI malignancies. Microsatellite-stable colorectal cancer and pancreatic adenocarcinoma, the most common GI tumors, have not benefited from treatment with standard immune checkpoint inhibitors. With this huge unmet need, multiple approaches are being tried to overcome barriers to better anticancer outcomes. This article reviews a number of novel approaches to immunotherapy for these tumors. These include the use of novel checkpoint inhibitors such as a modified anti-cytotoxic T lymphocyte-associated antigen-4 antibody and antibodies to lymphocyte-activation gene 3, T cell immunoreceptor with immunoglobulin and ITIM domains, T-cell immunoglobulin-3, CD47, and combinations with signal transduction inhibitors. We will discuss other trials that aim to elicit an antitumor T-cell response using cancer vaccines and oncolytic viruses. Finally, we review attempts to replicate in GI cancers the frequent and durable responses seen in hematologic malignancies with immune cell therapies.

Mismatch repair‐deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD‐L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β‐catenin, mitogen‐activated protein kinase, and TGF‐β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN‐γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan‐tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T‐cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T‐cell infiltrates coevolve in MMRd CRCs. Low T‐cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD‐L1 was expressed in the tumour microenvironment in most samples and correlated with T‐cell densities. However, PD‐L1 expression in cancer cells was independent of T‐cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD‐L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: It is widely believed that small rectal tumors are more likely to have a good response to neoadjuvant treatment, which may influence the selection of patients for a 'watch and wait' strategy. Objective: The aim of this study was to investigate whether there is a relationship between baseline tumor length on magnetic resonance imaging (MRI) and response to chemoradiotherapy. Method: The 96 patients with locally advanced rectal cancer randomised (2:1–intervention:control) in the TRIGGER feasibility study where eligible. Baseline tumor length was defined as the maximal cranio-caudal length on baseline MRI (mm) and was recorded prospectively at study registration. Magnetic resonance tumor regression grade (mrTRG) assessment was performed on the post-chemoradiotherapy (CRT) MRI 4–6 weeks (no later than 10 weeks) post completion of CRT. This was routinely reported for patients in the intervention (mrTRG-directed management) arm and reported for the purposes of this study by the central radiologist in the control arm patients. Those with an mrTRG I/II response were defined as 'good responders' and those with an mrTRG III–V response were defined as 'poor responders'. Results: Overall, 94 patients had a post-CRT MRI performed and were included. Forty-three (46%) patients had a good response (mrTRG I/II) and 51 (54%) patients had a poor response (mrTRG III/IV). The median tumor length of good responders was 43 mm versus 50 mm (p < 0.001), with considerable overlap in tumor lengths between groups. Conclusion: Baseline tumor length on MRI is not a clinically useful biomarker to predict mrTRG tumor response to CRT and therefore patient suitability for a deferral of surgery trial. [ABSTRACT FROM AUTHOR]

Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer progression. Moreover, leukocyte trafficking depended on the integrins CD11a/CD49d, and CD11a/CD49d blockade led to significant tumor burden reduction in mice. Importantly, preventing circulating Treg recruitment through depletion or sequestration in lymph nodes was sufficient to decrease tumor burden, indicating that Treg migration was crucial for suppressing antitumor immunity. These findings underscore the dynamic nature of the immune compartment within mouse lung tumors and demonstrate the relevance of a temporal map of leukocyte recruitment into tumors, thereby advancing our understanding of leukocyte migration in the context of tumor development., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs., Experimental Design: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination., Results: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer)., Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs., (©2019 American Association for Cancer Research.)