Restoring Anti-Tumor Immunity in Treatment-Refractory Gastrointestinal Cancers Restricted; Files Only
Phillips, Maggie (Spring 2025)
Abstract
Abstract
Restoring Anti-Tumor Immunity in Treatment-Refractory Gastrointestinal Cancers
By Maggie J. Phillips
Immunotherapy has transformed cancer treatment, with immune checkpoint inhibitors (ICIs) significantly improving survival rates in cancers with immunologically active TMEs (TMEs). However, their effectiveness is limited in "cold" tumors, which lack robust immune cell infiltration and are dominated by an immunosuppressive TME. These tumors pose considerable challenges due to factors including limited T cell infiltration, the presence of suppressive immune cell populations, dense fibrotic stroma that hinders immune cell access, and a high prevalence of microsatellite-stable (MSS) or proficient mismatch repair (pMMR) phenotypes. Overcoming these barriers requires novel therapeutic approaches that can modify the TME to support effective anti-tumor immune responses.
This research seeks to restore anti-tumor immunity in treatment-refractory gastrointestinal (GI) cancers by targeting key mechanisms of immunosuppression. Two complementary strategies are under investigation. The first strategy aims to enhance immune recognition in colorectal cancer (CRC) through Hsp90 inhibition and the promotion of a more immunogenic TME. The second strategy focuses on overcoming immune exclusion in PDAC by inhibiting CD26, thereby facilitating increased immune cell infiltration into the TME. These strategies were assessed in either preclinical or clinical studies to translate these findings to improve outcomes for patients facing these difficult-to-treat malignancies.
This first promising strategy involves Hsp90 inhibitors (Hsp90i), which have immunomodulatory effects on tumor cells. Hsp90 inhibition can enhance tumor antigen expression, improve immune recognition, and stimulate inflammatory responses, which fosters a more immunogenic environment. In a phase 1b/II clinical trial, XL888 (Hsp90i) was combined with pembrolizumab in patients with advanced GI cancer. The trial indicated this treatment combination was feasible, safe and well-tolerated. In this heavily pre-treated population of metastatic patients, no objective responses were observed, but 7 of 30 patients had disease stabilization. Notably, the regimen elicited unique immunomodulatory effects in metastatic liver tumors and systemic circulation. Further exploration of this combination as a neoadjuvant therapy or assessing its efficacy across different metastatic sites could help refine treatment strategies.
In addition to Hsp90i, another innovative strategy for enhancing anti-tumor immunity involves CD26 inhibitors. These inhibitors increase immune cell trafficking by inhibiting the cleavage of key chemokines and cytokines that guide immune cell migration. The CD26 inhibitors are FDA-approved drugs, commonly used to treat Type 2 Diabetes Mellitus1. They are well-tolerated and affordable, making them ideal candidates for repurposing as cancer therapies. Our preclinical studies are focused on two main areas. The first is assessing CD26 inhibition in in vivo orthotopic murine models of pancreatic ductal adenocarcinoma (PDAC) by evaluating changes in tumor burden and immune infiltration when combining sitagliptin (STG) with ICIs. We also aim to elucidate the role of CD26 in CAFs by measuring CD26 expression levels in CAFs and examining the invasive potential of PDAC cells in collagen matrices using 3D tumor-CAF spheroids, comparing CAFs wild-type (WT) vs. CD26 knockout (KO). For the orthotopic PDAC studies investigating STG with ICIs, we observed that this combination increased immune cell trafficking into the TME while simultaneously decreasing overall tumor burden. Furthermore, we discovered that CD26 KO CAFs significantly impairs the ability of cancer-associated fibroblasts (CAFs) to promote tumor growth and metastasis in our 3D tumor-CAF spheroids studies compared to the CD26 WT CAFs. This was likely mediated by reducing CAF-mediated extracellular matrix remodeling and decreasing CAF-mediated secretion of pro-tumorigenic factors.
These approaches highlight the potential for reprogramming the TME to improve immunotherapy outcomes in treatment-refractory GI cancers. By addressing the underlying mechanisms of immune exclusion, these strategies may pave the way for more effective treatments in cancers traditionally resistant to immunotherapy and enhance patient outcomes.
Table of Contents
Table of Contents
Abstract……………………………………………………………………………………….…..ii
Acknowledgements………………………………………………………………………....….vi
Table of Contents…………………………………………………………...…………....…….ix
List of Figures…………………………………………………………………...……………...xii
List of Tables…………………………………………………………………………….........xvii
List of Abbreviations…………………………………………………….……...……….........xix
Chapter 1: Introduction………………………………………………………………….……1
1.1 Revolutionizing Cancer Therapy Through Immunotherapy………….……......1
1.2 Mechanisms of Immunotherapy Resistance in CRC and PDAC: Immune Suppression and Stromal Barriers ……………………………………………..……..5
1.3 Advancing CRC and PDAC Treatment: From Standard of Care to Immunotherapy-Based Approaches…………………………………………………10
1.4. Reprogramming the Immune TME in CRC and PDAC: Targeting Hsp90 and DPP4/CD26……………………………………………………………………….……11
1.5. Summary, Scope, and Goals for this Project…………………………………18
Chapter 2: XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial…………………………….……………23
2.1 Abstract………………………………………………………...………………..…25
2.2 Key Findings…………………………...…………………………………………..26
2.3 Introduction……………………………………………………………….….…….27
2.4 Materials and Methods…………..………...………………………………..……29
2.5 Results…………………………………………………………………………......41
2.6 Discussion………………………………………………………..…………...…...69
2.7 Acknowledgements.……………………………………………………...….....…73
2.8 Declaration of Interest Statement………………………………………....…..…74
Chapter 3: Targeting CD26enzyme activity revitalizes immune checkpoint therapy by remodeling the immune TME in murine orthotopic models of pancreatic ductal adenocarcinoma…………………………………………………………………..……….…75
3.1 Abstract……………………………………………………………….…………....76
3.2 Key Findings……………………………...………………………………..………77
3.3 Introduction………………………………………………………………..……….78
3.4 Materials and Methods…………………………………………………..............82
3.5 Results………………………………………………………...……………………89
3.6 Discussion…………………………………………………………………..…....128
Chapter 4: Elucidating the role of CD26 in cancer-associated fibroblasts in pancreatic ductal adenocarcinoma ………………………………………………….….132
4.1 Abstract………………………………………………………………….……......133
4.2 Key Findings……………………………………………………………………...133
4.3 Introduction………………………………………...……………………..………134
4.4 Materials and Methods…………………………………………..…………...…137
4.5 Results……………………………………………………...………………..…...141
4.6 Discussion……………..............................................................................…156
Chapter 5: General Discussion and Closing Remarks………………..…………..…157
Chapter 6: References……………………………………..………………………………167
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