Supplementary Figure 4. Swimlane plots of treatment and clinical response.

Supplementary Table 5. Treatment-related serious adverse events.

Supplementary Figure 2. Relationship between plasma IL-6 levels and clinical response in the atezolizumab plus tocilizumab arm

Supplementary Table 7. Summary of serum concentrations and incidence of treatment-emergent antidrug antibodies.

Supplementary Table 4. Adverse events leading to any treatment discontinuation.

Supplementary Table 6. Grade 3-5 adverse events.

Supplementary Table 1. Patient disposition.

Advances in cancer prevention, early detection, and treatments have led to unprecedented progress against cancer. However, these advances have not benefited everyone equally. Because of a long history of structural inequities and systemic injustices in the United States, many segments of the US population continue to shoulder a disproportionate burden of cancer. The American Association for Cancer Research (AACR) Cancer Disparities Progress Report 2024 (CancerDisparitiesProgressReport.org) outlines the recent progress against cancer disparities, the ongoing challenges faced by medically underserved populations, and emphasizes the vital need for further advances in cancer research and patient care to benefit all populations.

Cytokines mediating epithelial and immune cell interactions modulate mucosal healing- a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing, flow cytometry, and co-immunoprecipitation identified FAS as the predominant colonic epithelial receptor for TNFSF13. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in the production of IgA+ plasma cells compared to control colonoid co-cultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming ther-apeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder can-cers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R defi-ciency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.

BACKGROUND & AIMS:The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration. METHODS:We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein IGF2 messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of Atg7. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization. RESULTS:Epithelial Imp1 deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of Atg7 reversed the enhanced regeneration observed with Imp1 deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with MAP1LC3B transcripts at homeostasis. Stress induction led to decreased colocalization. CONCLUSIONS:Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.

Calorie restriction is associated with enhanced intestinal regeneration after irradiation, but the requirement of autophagy for this process is not known. Our data support the premise that intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction. We also report that luminal levels of primary bile acid glycocholic acid are modulated by epithelial cell autophagy during calorie restriction with direct effects on epithelial stem cell function.

AbstractPurpose: The MORPHEUS platform was designed to identify early efficacy signals and evaluate the safety of novel immunotherapy combinations across cancer types. The phase Ib/II MORPHEUS-UC trial (NCT03869190) is evaluating atezolizumab plus magrolimab, niraparib, or tocilizumab in platinum-refractory locally advanced or metastatic urothelial carcinoma (mUC). Additional treatment combinations were evaluated and will be reported separately. Patients and Methods: Patients had locally advanced or mUC that progressed during or following treatment with a platinum-containing regimen. The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoints included investigator-assessed progression-free survival (PFS) and overall survival (OS). Safety and exploratory biomarker analyses were also conducted. Results: Seventy-six patients were randomized to receive either atezolizumab plus magrolimab (n = 16), atezolizumab plus niraparib (n = 15), atezolizumab plus tocilizumab (n = 15), or atezolizumab monotherapy (control; n = 30). No additive benefit in ORR, PFS, or OS was seen in the treatment arms versus the control. The best confirmed ORR was 26.7% with atezolizumab plus magrolimab, 6.7% with atezolizumab plus niraparib, 20.0% with atezolizumab plus tocilizumab, and 27.6% with atezolizumab monotherapy. Overall, the treatment combinations were tolerable, and adverse events were consistent with each agent's known safety profile. Trends were observed for shrinkage of programmed death-ligand 1–positive tumors (atezolizumab, atezolizumab plus magrolimab, atezolizumab plus tocilizumab), inflamed tumors, or tumors with high mutational burden (atezolizumab), and immune excluded tumors (atezolizumab plus magrolimab). Conclusions: The evaluated regimens in MORPHEUS-UC were tolerable. However, response rates for the combinations did not meet the criteria for further development in platinum-experienced locally advanced or mUC.

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.

The annual American Association for Cancer Research (AACR) Cancer Progress Report is a cornerstone of AACR's efforts to educate the public and Congress about the latest advances against cancer and the importance of medical research and to advocate for increased federal funding for the NIH, NCI, FDA, and CDC.This 13th edition of the report, which covers the 12-month period from August 1, 2022, to July 31, 2023, documents how breakthroughs across basic, translational, and clinical research and population sciences have advanced the frontiers of cancer science and medicine. This report, and all previous editions, are freely available at https://cancerprogressreport.aacr.org/progress/.There has been remarkable progress against cancer in the United States, which has led to a steady decline in the overall cancer mortality rate. Between 1991 and 2020, the age-adjusted overall cancer mortality rate declined by 33%, a reduction that translates into 3.8 million cancer-related deaths avoided. The decline in cancer mortality can be attributed largely to improvements in prevention, early detection, and treatment, with the most progress made against cancers of breast, prostate, colon and rectum, as well as against previously intractable cancers such as advanced lung cancer and metastatic melanoma.Research in basic sciences is vital to our knowledge of how cancers develop. Advances in basic research along with technological innovations have led to a revolution in molecular profiling approaches such as spatial transcriptomics while also expanding the applications of proteomics and epigenetics to further our understanding of the complex disease we call cancer.Advancements in the areas of cancer prevention and early detection are helping to reduce the risk of cancer development. Forty percent of all cancers in the United States are attributable to preventable causes. Modifying behaviors such as eating a healthy diet and participating in physical activity, refraining from tobacco use, managing chronic conditions such as diabetes and infections, receiving recommended immunizations to prevent pathogenic infections such as those with the human papillomavirus (HPV), and protecting skin from UV radiation are ways to reduce the risk of developing cancer.Screening for breast, prostate, cervical, colorectal, and lung cancer has helped to reduce mortality from these cancers. Cancer screening recommendations are developed for individuals who are at an average or higher-than-average risk of being diagnosed with cancer and are based on gender and age, as well as genetic, environmental, behavioral, and social influences. Notably, during the 12 months covered in the report, the United States Preventive Services Task Force issued a draft recommendation for breast cancer screening to lower the age of eligible individuals from 50 to 40, which is estimated to save 19% more lives from breast cancer. New technologies, including artificial intelligence and liquid biopsies, that are rapidly moving from the bench to the clinic have the potential to improve detection of early-stage cancers or precancerous lesions while potentially increasing safety of screening tests. Although liquid biopsy–based tests have shown great potential for early detection of cancer, large prospective studies must demonstrate that screening using these methods can extend lives before they can be used routinely in the clinic.The report documents major progress made across the five pillars of cancer treatment – surgery, radiotherapy, cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy. Between August 1, 2022, and July 31, 2023, the FDA approved 14 new anticancer therapeutics (Table 1) and two new imaging agents and expanded the use of 12 previously approved anticancer therapeutics to treat additional cancer types. Included in the FDA approvals are the first antibody–drug conjugate for the treatment of ovarian cancer, multiple new immunotherapeutics to treat rare cancers including blood cancers, two new immune checkpoint inhibitors, and a first-of-its-kind gene therapy to treat bladder cancer. Decades of basic and translation research in immunology and cancer biology is fueling a surge in the applications of immunotherapy, one of the most exciting new areas in cancer medicine, as highlighted in a spotlight in the report titled "Immunotherapy: Pushing the Frontier of Cancer Medicine." Furthermore, precision medicine approaches are leading to the development of personalized treatments for patients with previously intractable cancers such pancreatic cancer and glioblastoma.Advances across the cancer continuum have led to many more people living with and beyond their cancer. As of January 1, 2022, there are more than 18 million people living with a history of a cancer diagnosis, which equates to about 5% of the U.S. population. Understanding and addressing their physical, psychosocial, and financial challenges are important priorities as the number of survivors in the United States is expected to grow to 26 million by 2040. Innovative approaches in the areas of palliative care, psycho-oncology, new technologies such as mobile phone apps that help with continuity of care, and other evidence-based strategies that improve quality of life are active areas of research. Coordination of care using patient navigators and patient advocates as well as the increased use of patient reported outcomes, specifically in clinical trial research, are collectively improving the survivorship experience. It is estimated that 4 million individuals in the United States are caring for an adult with cancer. Supporting these caregivers by addressing their physical, psychologic, and financial needs is also paramount.Despite major progress, cancer continues to be an ongoing public health challenge. In the United States, a disproportionate burden of cancer is shouldered by patients from racial and ethnic minorities and other medically underserved populations. If we are to achieve the President's Cancer Moonshot goal of reducing the U.S. cancer-related death rate by 50% by the year 2047, continued federal investments in NIH, NCI, FDA, and CDC must be secured to sustain the momentum of scientific progress. The returns on these investments have been extraordinary. As one example, patients with cancer in the United States have collectively gained nearly 14 million years of life since 1980, thanks to the clinical research funded by NCI.Therefore, AACR urges Congress for its unwavering and historically bipartisan support to make medical research a long-term strategic priority for our nation. All stakeholders in the cancer research and care community can seize today's unprecedented scientific opportunities to advance the frontiers of cancer science and medicine for the benefit of all patients with cancer.No disclosures were reported.

Homeostatic tissue maintenance requires coordinated regulation of metabolic processes including macroautophagy/autophagy. Autophagy dysregulation underlies numerous human diseases. Our prior work revealed that the RNA binding protein IGF2BP1/IMP1 binds transcripts encoding autophagy-related proteins. Furthermore, Imp1 deletion in gastrointestinal epithelial cells in mice was associated with enhanced autophagy flux and improved recovery from tissue injury. In the current study, we evaluated molecular mechanisms underlying IMP1 modulation of autophagy. We provide a mechanism of direct IMP1 regulation of MAP1LC3B that is dependent upon IMP1 phosphorylation or cell stress, suggesting dynamic modulation of Imp1-mediated autophagy repression that facilitates tissue regeneration. More broadly, our study supports a new mechanism by which tissue regeneration is modulated post-transcriptionally via cell state rather than changes in stem or other cell lineages. This new mechanism may be particularly important in gastrointestinal epithelial cells, where autophagy is essential for tissue recovery following injury, or in diseases such as inflammatory bowel disease where defective autophagy is implicated.

Homeostatic tissue maintenance requires coordinated regulation of metabolic processes including macroautophagy/autophagy. Autophagy dysregulation underlies numerous human diseases. Our prior work revealed that the RNA binding protein IGF2BP1/IMP1 binds transcripts encoding autophagy-related proteins. Furthermore, Imp1 deletion in gastrointestinal epithelial cells in mice was associated with enhanced autophagy flux and improved recovery from tissue injury. In the current study, we evaluated molecular mechanisms underlying IMP1 modulation of autophagy. We report increased expression of autophagy protein microtubule associated protein 1 light-chain 3B (MAP1LC3B) in cells with IMP1 deletion compared to control cells. MAP1LC3B expression was also increased in cells with mutated IMP1 phosphorylation sites. Luciferase reporter assays demonstrate increased translation of MAP1LC3B-3’UTR in cells with IMP1 deletion. Furthermore, we find that IMP1 co-localizes with MAP1LC3B transcripts at homeostasis, and co-localization is decreased in cells where IMP1 phosphorylation sites are mutated. IMP1 localization with MAP1LC3B transcripts is also decreased following cell stress. Taken together, our data support a model whereby IMP1 regulates MAP1LC3B translation which can serve as a mechanism to calibrate autophagy levels in the cell. This new mechanism may be particularly important in gastrointestinal epithelial cells, where autophagy is essential for tissue recovery following injury, or in diseases such as inflammatory bowel disease where defective autophagy is implicated.