Immunotherapy has redefined what’s possible in cancer care, improving both the length and quality of life for many patients. But cancer’s adaptability means not everyone benefits equally, and researchers are working hard to change that. At the recent AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy in Boston, held October 18-21, scientists explored advances in current immunotherapy approaches, and focused on how the tumor microenvironment and gut bacteria influence cancer progression and our strategies to overcome cancer.
The message was clear: To crack cancer’s code, we need a deeper understanding of its interaction with the immune system.
Susan Kaech, PhD, director of the NOMIS Center for Immunobiology and Microbial Pathogenesis at the Salk Institute for Biological Studies, started her opening keynote with a fascinating look at the metabolic environment of tumors, focusing on liver cancer. Kaech’s team, in work led by Karthik Varanasi, PhD, found that elevated primary bile acids in human and murine liver cancer can disrupt the tumor-reactive T cells, key players in the anticancer immune response. By targeting the BAAT enzyme involved in bile acid production, this reduced tumor burden and enhanced T-cell infiltration and antitumor immunity in preclinical models, potentially opening new doors for liver cancer treatment.
Interestingly, not all bile acids were found to be harmful—one of the secondary bile acids, ursodeoxycholic acid, which is created by the microbiome, even showed protective effects on reducing tumor burden when given to mice in the diet. These findings highlight the complex metabolic ecosystems within tumors and suggest that other organs might also have unique metabolic vulnerabilities.
“When tumors co-opt cells in the local environment to fuel their growth, they may be hijacking, or putting into overdrive, a natural homeostatic relationship that existed before,” Kaech noted. “By considering the metabolic state of the tissue and its needs before it became cancerous, we may identify weak points in the tumor’s metabolism. This is because some aspects of the original metabolic function might still be reflected in the tumor’s current behavior.”
Kaech next delved into how T cells metabolize nutrients as they develop and differentiate. In work led by Shixin Ma, PhD, they discovered that T cells, in order to differentiate into specific states, rely on specific enzymes (ACSS2 and ACLY) to catalyze the production of acetyl coenzyme A (acetyl-CoA) from different nutrient sources. In particular, progenitor exhausted T cells, which are crucial for long-term immunity and responses to immune checkpoint blockade, were found to prefer acetate as a source, whereas more dysfunctional, terminally exhausted T cells relied on glucose. Perhaps most surprisingly, simply knocking out the enzyme that converts glucose to acetyl-CoA enhanced progenitor T-cell formation and antitumor immune responses in mice.
These enzymes are found in the nucleus, but their role there is not well understood. Kaech and Ma discovered that ACSS2 and ACLY work with different enzymes in the nucleus to modify histones and change the chromatin accessibility at certain sites in the genome. This, in turn, affected the expression of specific genes linked to T-cell states. Whereas ACSS2 used acetate to increase acetylation and expression of genes for early-stage exhausted T cells, ACLY used citrate to boost acetylation and expression of genes for fully exhausted T cells. This showed a key connection between how cells use nutrients and the types of genes they activate, and could lead to strategies for manipulating T-cell states to enhance the potency and persistence of antitumor responses.
“Initially, we thought which enzymes are utilized to produce acetyl-CoA probably wouldn’t matter, and that the total acetyl-CoA pool would be what matters most to the cells, but we got a different answer,” Kaech acknowledged.
These findings presented an important chicken-or-the-egg-like conundrum that could have significant implications for the development of future immunotherapies: What ultimately drives T-cell differentiation, the availability of nutrients or enzymes?
“We have no definitive evidence for either one right now, but what we can certainly say is that if you manipulate the enzymes, you will affect the differentiation state,” she said.
Doubling Down on Immunotherapy, Earlier
In his closing keynote, Ton Schumacher, PhD, senior member of the Netherlands Cancer Institute, discussed the immense potential of using immune checkpoint inhibitors (ICIs) prior to surgery. He first described data from the OpACIN study that provided the first evidence for the superior immune activating capacity of immune checkpoint inhibition prior to surgery. Subsequently, he discussed the phase II NICHE-2 clinical trial that tested two ICIs, nivolumab and ipilimumab, in patients with newly diagnosed colorectal cancer (CRC) defined by deficient DNA mismatch repair (dMMR).
The results were promising: Nearly all patients had a significant reduction in tumor cells at the time of surgery, and none experienced relapse after three years follow-up. Historically, around 40% of those with high-risk, stage 3 dMMR CRC experience disease recurrence within three years, even with adjuvant chemotherapy, prompting Schumacher to declare that “these data make a very strong case for this treatment strategy.”
“Immune checkpoint blockade only boosts T-cell activation when antigen is present,” Schumacher explained. “Therefore, blocking these inhibitory receptors only makes sense when an activating signal—the target antigen—is present at the same time.”
Thus, our fundamental understanding of immune checkpoint function tells us that ICIs might be far more effective when used prior to surgery.
“It’s like releasing your car’s handbrake, where nothing happens unless you also hit the gas,” Schumacher said. “After surgery, there will be minimal antigen to drive T-cell activity. On the contrary, when checkpoint blockade is initiated prior to surgery, antigen from that entire tumor mass is present to drive T-cell activity, which can then hopefully persist even after the bulk of the tumor and antigen have been removed.”
“The Grand Challenge”: Cracking the T Cell Code
To close his keynote, Schumacher discussed his team’s progress in addressing what he termed “The Grand Challenge” in cancer immunology of understanding precisely what T cells “see” when they recognize cancer cells.
When T cells bind a cancer cell, they engage a specific antigen presented by a major histocompatibility complex (MHC) molecule on the cancer cell’s surface. This interaction, called a TCR-pMHC pairing, involves three key components: the T-cell receptor (TCR), the peptide antigen (which is what the p stands for), and the MHC molecule (also known as HLA in humans). While this may sound straightforward, Schumacher highlighted the staggering complexity of efforts to decode this puzzle in patients.
Each individual, according to Schumacher, has an estimated 100 billion possible T-cell receptors. On top of that, humans have more than 10,000 unique HLA variants for MHC class I alone. These HLA molecules can present over 1 trillion different antigen fragments, creating a vast number of potential TCR-pMHC pairings. Understanding which pairings lead to effective T-cell responses is critical for developing personalized immunotherapies, but represents an immense data and manufacturing problem.
PAIR-Scan, a new tool developed by Schumacher’s team, is designed to tackle this complexity. Using patient samples, PAIR-Scan creates synthetic libraries that mimic the diversity of both TCRs and pMHCs in a given individual. By screening these libraries against each other, researchers can identify which specific TCR-pMHC interactions trigger the strongest cancer-killing response. As a proof-of-concept, Schumacher’s team used PAIR-Scan to identify several immunologically significant TCR-pMHC pairs in a melanoma patient.
Looking ahead, this technology’s ability to design and customize synthetic T cells more efficiently also hints at its potential to improve how we create personalized, scalable T-cell therapies for solid tumors, which remain challenging to treat with existing T-cell therapies.
“We require a lot of clever engineering,” Schumacher concluded, “which reinforces my view that immuno-oncology is as much an engineering discipline as it is a biomedical one.”
The Future of tumor immunology and Immunotherapy
The AACR Tumor Immunology and Immunotherapy conference made one thing clear: we are standing on the cusp of a new era in cancer treatment. The complex dance between tumors and the immune system continues to reveal hidden vulnerabilities and new therapeutic opportunities. From leveraging metabolic ecosystems in liver cancer to cracking the intricate T-cell recognition code, these breakthroughs highlight the power of precision science and innovative engineering.
As researchers like Kaech and Schumacher push the boundaries of tumor immunology and immunotherapy, the future holds immense promise. By refining our understanding of the immune system’s role in cancer and harnessing cutting-edge technologies like PAIR-Scan, the field aims to usher in an era of truly personalized medicine.
The journey is far from over, but with each discovery, we edge closer to a future where immunotherapy works for every patient, regardless of their tumor’s tricks.
