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CICON19 Day 4 Update: Metabolic Crosstalk and the Microbiome

September 28, 2019

Session 11: Immuno-Oncology Crosstalk and Metabolism

The final day of CICON19 began with a talk by Greg M. Delgoffe, Ph.D., of the University of Pittsburgh, who focused on how metabolism influences T cell exhaustion in the tumor microenvironment. Delgoffe showed that chronic antigen stimulation under low oxygen conditions (referred to as hypoxia) led to a buildup of reactive oxygen species (ROS) in T cells that drove them toward an exhausted, dysfunctional state. This state was also characterized by the loss of functional mitochondria, which correlates with resistance to PD-1 checkpoint immunotherapy. An apparent culprit in this transformation is Blimp-1-mediated repression of PGC1a, which otherwise plays a key role in mitochondrial growth. When T cells lacked Blimp-1, they were resistant to exhaustion when continuously stimulated under hypoxia, and also retained their mitochondrial mass and expression of PGC1a. Importantly, disrupting hypoxia enabled clearance of ROS and made tumors more susceptible to PD-1 immunotherapy.

Greg M. Delgoffe, Ph.D., discusses how metabolism influences T cell exhaustion in the tumor microenvironment at CICON19
Greg M. Delgoffe, Ph.D., discusses how metabolism influences T cell exhaustion in the tumor microenvironment.

For the second part of his talk, Delgoffe examined regulatory T cells (Tregs), which he found possess a distinct metabolic profile that allows them to thrive in the tumor microenvironment. In fact, the most immunosuppressive Tregs were characterized by reduced uptake of glucose and an apparent preference for lactate, which is produced by proliferating cancer cells and is used by Tregs as an energy source as well as a building block for macromolecules. When Tregs were prevented from consuming lactate, they became functionally unstable and less proliferative, allowing for enhanced activity of “killer” T cells within tumors. To address this phenomenon in the clinic, Delgoffe suggested bolstering the support for “killer” T cells by disrupting hypoxia, and breaking the metabolic relationships whereby tumors “feed” suppressive Treg cells.

PSGL-1 is another signaling pathway that influences T cell exhaustion in the context of cancer, according to Jennifer L. Hope, Ph.D., of the Sanford Burnham Prebys Medical Discovery Institute. Without PSGL-1 signaling, Hope showed, T cells become less exhausted, express lower levels of PD-1, and are associated with better control of tumor growth. In these circumstances, tumors contained more polyfunctional “killer” T cells as well as more effector “helper” T cells compared to immune-suppressing Tregs. Upon further examination, she found that tumor-specific “killer” T cells lacking PSGL-1 had increased expression of metabolism-related genes and were highly energetic. This deficiency also made these T cells more sensitive to activation of their T cell receptors (TCRs)—after which they increased their uptake of glucose—and even as this activation waned, they still produced increased amounts of important cytokines. Moving forward, Hope aims to identify the mechanistic links between PSGL-1 deficiency, TCR signaling, and increased glucose metabolism.

Jennifer L. Hope, Ph.D., discusses PSGL-1 signaling at CICON19
Jennifer L. Hope, Ph.D., discusses PSGL-1 signaling.

The following talk, by Ursula Grohmann, Ph.D., of the University of Perugia (Italy), focused on the IDO1 protein. In addition to its enzymatic role in the degradation of the amino acid tryptophan, Grohmann showed that IDO1 also acts as an intracellular signaling molecule that can induce regulatory (immune-suppressing) behavior in plasmacytoid dendritic cells. Some inhibitors of IDO1’s enzymatic activity appear to make these dendritic cells more immunosuppressive, possibly by skewing IDO1’s activity in the direction of its signaling activity. Therefore, she suggested, inhibiting this signaling activity of IDO1 may be more beneficial in the context of cancer than inhibiting its enzymatic activity. To this end, one agent—VIS-128—led to a reduction in IDO1’s signaling-related interactions and made dendritic cells better at stimulating immune activity.

Ursula Grohmann, Ph.D., discusses the IDO1 protein at CICON19
Ursula Grohmann, Ph.D., discusses the IDO1 protein.

Next, James L. Reading, Ph.D., of University College London, spoke about his work in the lab of former CRI postdoctoral fellow Sergio Quezada, Ph.D., where he is exploring the hypothesis that mutated tumor neoantigens drive the activation and differentiation of T cells in lung cancer. Reading found that as tumor mutational burden (TMB) increased, so did the activation of “killer” T cells and the diversity of the T cell receptor repertoire within tumors. Similarly, increasing numbers of mutated tumor neoantigens increased were associated with a redistribution of “killer” T cell subsets characterized by the loss of early differentiated and memory T cell pools, and increased proportion of dysfunctional T cells. This trend was observed in both “killer” and “helper” T cells, and highlights how, as tumors become more immunogenic (immune-stimulating), chronic antigen stimulation can also render T cells less effective by promoting exhaustion and terminal differentiation.

James L. Reading, Ph.D., discusses how mutated tumor neoantigens drive the activation and differentiation of T cells at CICON19
James L. Reading, Ph.D., discusses how mutated tumor neoantigens drive the activation and differentiation of T cells.

In ovarian cancer, another way that tumors can promote immune dysfunction is through constant stress associated with an intracellular component called the endoplasmic reticulum (ER), according to Chang-Suk Chae, Ph.D., a CRI postdoctoral fellow at Weill Cornell Medicine who works in the lab of CRI CLIP Investigator Juan R. Cubillos-Ruiz, Ph.D. A hostile tumor microenvironment appeared to be the source of this ER stress, which, if sustained, enabled reprogramming of cancer cells via the IRE1a and XBP1 signaling pathways. This not only promoted tumor growth, but also made tumors more resistant to chemotherapy and more prone to metastasize or spread to other tissues. Immune cells within the tumor are also affected by this chronic stress. In particular, the function of dendritic cells was inhibited, while their production of prostaglandin E2 (PGE2) was increased.

Chang-Suk Chae, Ph.D., discusses endoplasmic reticulum stress at CICON19
Chang-Suk Chae, Ph.D., discusses endoplasmic reticulum stress.

However, when intratumoral dendritic cells lacked the transcription factor XBP1, their metabolic activity was restored, increasing their antigen-presenting capability and improving their ability to activate effector T cells and promote anti-tumor immune responses. These XBP1-deficient dendritic cells didn’t produce PGE2 either and were associated with a decrease in the accumulation of immune-suppressing regulatory T cells within the tumor. Lastly, Chae showed that vaccinating mice with XBP1-deficient dendritic cells increased the number of tumor-infiltrating T cells—both “killer” and “helper”—and was able to control progression of metastatic ovarian cancer, ultimately improving the survival of these mice.

Session 12: Microbiota in Oncoimmunology

The final session of CICON19 focused on one of the more cutting-edge areas related to cancer immunotherapy: the impact of the microbiome—the collection of microbial organisms, including bacteria, within us. Laurence Zitvogel, M.D., Ph.D., of Gustave Roussy Cancer Center (France), kicked off the session by highlighting recent findings that T cell responses against the bacteria E. hirae were associated with increased overall survival in patients with lung and kidney cancer, whether they were treated with chemotherapy or PD-1 immunotherapy. Probing more deeply, Zitvogel showed that at least one strain of E. hirae could induce memory T cell responses against itself. This immune stimulation appeared to be directed against a protein—known as TMP1—produced by a virus that infects the bacteria, as TMP1 itself could reproduce the immune-stimulating capabilities of the whole bacteria.

Laurence Zitvogel, M.D., Ph.D., discusses the bacteria E. hirae at CICON19
Laurence Zitvogel, M.D., Ph.D., discusses the bacteria E. hirae.

When E. coli was engineered to express TMP1, they, too, became immune-stimulating. In humans, patients whose stool contained the TMP1-expressing bacteria were found to respond better to PD-1 immunotherapy. Interestingly, TMP1 was shown to be very similar—molecularly speaking—to a portion of the tumor suppressor protein GPD1-L, and patients with bladder, kidney, or lung cancer whose tumors expressed high levels of GPD1-L experienced longer protection against disease progression after being treated with PD-1 immunotherapy. Thus, Zitvogel suggested, perhaps future strategies could aim to induce TMP1 expression in our inner bacteria in order to stimulate immune responses that could then be harnessed against patients’ tumors.

Following Zitvogel, CRI postdoctoral fellow Duncan R. McKenzie, Ph.D., of The Francis Crick Institute (United Kingdom), spoke about how immune cells called gamma-delta T cells conduct immune surveillance on the skin. In particular, these T cell engage a molecule called Skint1 that regulates the homeostasis of epidermal skin cells. McKenzie showed that this Skint1 molecule is required for gamma-delta T cells’ ability to survey the skin for signs of stress and that it maintains their sensitivity to 4-1BB signaling. However, in the presence of stress—mediated by as-yet unknown signals—the lack of Skint1 signaling stimulates these gamma-delta T cells to produce molecules called granzymes that can mediate cell killing. As McKenzie seeks to learn more about the mechanisms that stimulate these gamma-delta T cells, he hopes that they may provide a promising source of immune cells for adoptive cell immunotherapy and potentially other immune-based approaches against cancer.

Duncan R. McKenzie, Ph.D., discusses gamma-delta T cells and immune surveillance at CICON19
Duncan R. McKenzie, Ph.D., discusses gamma-delta T cells and immune surveillance. 

Speaking next was Giorgio Trinchieri, M.D., a CRI Scientific Advisory Council member at the National Cancer Institute. Trinchieri’s talk focused on better ways to target the microbiome to improve immunotherapy responses in patients, as several groups have shown that certain bacteria are associated with improved likelihood of response to PD-1 immunotherapy. To that end, Trinchieri highlighted trials that are exploring a number of microbiome-based treatments—including an orally available pill as well as fecal microbiota transplants (FMT). Trinchieri also highlighted recent findings—done in collaboration with Jennifer A. Wargo, M.D., of the University of Texas MD Anderson Cancer Center, who spoke later in the session—on how dietary fiber intake affects responses to PD-1 immunotherapy.

Giorgio Trinchieri, M.D., discusses targeting the microbiome to improve immunotherapy responses at CICON19
Giorgio Trinchieri, M.D., discusses targeting the microbiome to improve immunotherapy responses.

Thus far, those with high-fiber intake were enriched in the responder group, while those with low-fiber intake were less likely to respond. In preclinical experiments in mice, Trinchieri showed that diet dramatically changes the microbiome composition in mice. Here too, fiber improved responses to PD-1 immunotherapy. Interestingly, in these studies “killer” T cell expression of ICOS—an important co-stimulatory pathway—correlated with PD-1 responses. Moving forward, Trinchieri stressed the need to discover microbiome-related biomarkers to better predict patient responses to treatment, clarify exactly which bacterial species improve responses and how, and identify how diet and other factors are able to induce or maintain a beneficial microbiome in patients.

Next, Chengcheng Jin, Ph.D., of the Massachusetts Institute of Technology, presented the results of her investigations into the interactions between the immune system and bacteria in lung cancer. In addition to showing that antibiotics were able to inhibit tumor development and progression, Jin found that the development of lung cancer was associated with an increase in the amount of bacteria within lung tissue and that the composition of these bacterial species was altered. These tumor-promoting bacteria also stimulated the proliferation and activation of IL-17 expressing gamma-delta T cells via the IL-1b and IL-23 pathways. When the activity of these T cells or IL-17 signaling was blocked, it suppressed tumor growth and the infiltration of neutrophils into tumors without affecting the conventional “killer” and “helper” T cells within tumors.

In the future, Jin will seek to identify the specific tumor-promoting components of these bacteria and characterize how tumors, in turn, influence the local microbiome composition. Additionally, we must still learn how gut bacteria influence the development of lung cancer and responses to immunotherapy as well as if any other types of immune cells are involved in these processes.

Chengcheng Jin, Ph.D., discusses bacteria within lung tissue at CICON19
Chengcheng Jin, Ph.D., discusses bacteria within lung tissue.

The finale speaker of the session—and of CICON19 overall—was Jennifer A. Wargo, M.D., of the University of Texas MD Anderson Cancer Center, who highlighted the “yin and yang” of bacteria within tumors—that while some contribute to cancer development and resistance to treatment, others seem to improve patient responses. As a result, they may be able to serve as important biomarkers and potentially even therapeutic targets moving forward. The gut microbiome also appears to play an important role in how tumors outside the intestines respond to immunotherapy, and is being targeted in clinical trials.

Jennifer A. Wargo, M.D., discusses the importance of identifying an optimal consortia of bacteria at CICON19
Jennifer A. Wargo, M.D., discusses the importance of identifying an optimal consortia of bacteria.

Discussing one of the trials referenced earlier by Trinchieri, Wargo highlighted encouraging results seen with the combination of FMT and PD-1 immunotherapy in patients with metastatic melanoma for whom PD-1 immunotherapy was previously ineffective. She then went on to stress, like others, the importance of identifying an optimal consortia of bacteria that can improve responses to immunotherapy, pointing to several promising results made in preclinical models. These insights are now being incorporated into clinical trials, too. In addition to observing differences in the microbiome between responders and non-responders, Wargo also noted that differences have been found between healthy people and cancer patients as well as between patients with late-stage disease versus those with early-stage disease. Near the end of her talk, Wargo stressed that as more is learned about how factors such as diet and probiotics affect outcomes, doctors will have an obligation to advise their patients accordingly in order to help promote better outcomes for them.

That’s all for CICON19 but be sure to check back on our blog soon for other updates on advances in the field of cancer immunotherapy, and remember to join us in New York City for CICON20!

Dr. Wargo mentioned that Dr. Zitvogel served as an inspiration to her in this field and presented her with a framed picture at CICON19
Dr. Wargo mentioned that Dr. Zitvogel served as an inspiration to her in this field and presented her with a framed picture. 

All photos by Arthur N. Brodsky, Ph.D., for the Cancer Research Institute

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