ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors

Hong, Yun Sik; Walling, Brandon L.; Kim, Hye‐Ran; Serratelli, William S.; Lozada, John; Sailer, Cooper J.; Amitrano, Andrea M.; Lim, Kihong; Mongre, Raj Kumar; Kim, Kyun-Do; Capece, Tara; Lomakina, Elena B.; Reilly, Nicholas S.; Vo, Kevin D.; Gerber, Scott A.; Fan, Tan‐Chi; Yu, Alice L.; Oakes, Patrick W.; Waugh, Richard E.; Jun, Chang‐Duk; Reagan, Patrick M.; Kim, Minsoo

doi:10.1038/s41590-023-01498-x

Cited by 19 publications

(13 citation statements)

References 53 publications

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“…7B and Supplementary Fig. 10A ), consistent with the notion that the lungs are a particularly favorable site for T cell infiltration 49 . However, we observed that Rapa-CD8 CAR cells were significantly more accumulated in tumor islets compared with ctrl-CD8 CAR cells, which remained largely in the surrounding stroma (Fig.…”

Section: Resultssupporting

confidence: 85%

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Simula,

Fumagalli,

Vimeux

et al. 2024

Nat Commun

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The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

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Section: Resultssupporting

confidence: 85%

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Simula,

Fumagalli,

Vimeux

et al. 2024

Nat Commun

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show abstract

“…7B and Fig. S10A ), consistent with the notion that the lungs are a particularly favorable site for T cell infiltration 48 . However, we observed that Rapa-CD8 CAR cells were significantly more accumulated in tumor islets compared with ctrl-CD8 CAR cells, which remained largely in the surrounding stroma ( Fig.…”

Section: Resultssupporting

confidence: 84%

“…7E ). The morphology of TME is altered in this model compared with the orthotopic one (tumor cells do not accumulate in stroma-surrounded islets but in large areas with fewer adjacent stroma) and vasculature is more deregulated (as frequently observed in human solid tumors 49 ), making CAR T cell infiltration more difficult compared with lungs 48 . Mice were i.v.…”

Section: Resultsmentioning

confidence: 92%

Mitochondrial metabolism sustains CD8⁺T cell migration for an efficient infiltration into solid tumors

Simula,

Fumagalli,

Vimeux

et al. 2024

Preprint

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The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a much minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cells intra-tumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

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“…They determined that ST3GAL1 altered lymphocyte function‐associated antigen‐1 (LFA‐1) endocytic recycling and that this could be overcome by enhanced expression of betaII‐spectrin, a central LFA‐1‐associated cytoskeleton molecule. Indeed, CAR T cells overexpressing betaII‐spectrin demonstrated improved tumor homing and tumor control 64 . Notably, our collaborator Prof. Christoph Hess recently demonstrated a role for magnesium sensing by LFA‐1 and the regulation of T‐cell effector function, including of CAR T cells 356 …”

Section: T‐cell Coengineering Strategies To Augment Tumor Controlmentioning

confidence: 97%

“…Important advances are rapidly being made for improving the efficiency of CRISPR‐based engineering 56–61 poised to revolutionize immunotherapy through cellular reprogramming of T cells 56 . Indeed, CRISPR screens (both loss‐ and gain‐of‐function experiments) have enabled important discoveries including the identification of key regulators of T‐cell activities such as proliferation in response to stimulation, 62 gene networks controlling IL‐2 and IFN‐γ production, 63 genes that can be targeted to improve T‐cell trafficking to tumors 64 or alleviate exhaustion, 65–67 and new tumor‐specific receptors 68 . Importantly, advanced gene‐editing tools such as CRISPR are paving the way towards off‐the‐shelf allogeneic T‐cell products that can overcome graft‐versus‐host disease (GVHD) and host allorejection, and which should substantially decrease the costs of cellular therapies, enable treatment of heavily pretreated patients (i.e., the patients may be lymphopenic and not have sufficient T cells), and allow rapid delivery of a more uniform T‐cell product 69 .…”

Section: Tools For Coengineering T Cellsmentioning

confidence: 99%

Coengineering specificity, safety, and function into T cells for cancer immunotherapy

Giordano Attianese,

Ash,

Irving

2023

Immunological Reviews

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SummaryAdoptive T‐cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene‐modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer‐types. The field of ACT has been driven forward by the clinical success of CD19‐CAR therapy against various advanced B‐cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non‐hematological solid tumors. Indeed, in addition to pre‐infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post‐transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T‐cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down‐regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity‐optimized TCRs can improve T‐cell function and innovative CAR designs as well as gene‐modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T‐cell coengineering strategies, including of tools, receptors, and gene‐cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.

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ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors

Cited by 19 publications

References 53 publications

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Mitochondrial metabolism sustains CD8⁺T cell migration for an efficient infiltration into solid tumors

Coengineering specificity, safety, and function into T cells for cancer immunotherapy

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ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors

Cited by 19 publications

References 53 publications

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Mitochondrial metabolism sustains CD8+T cell migration for an efficient infiltration into solid tumors

Coengineering specificity, safety, and function into T cells for cancer immunotherapy

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Mitochondrial metabolism sustains CD8⁺T cell migration for an efficient infiltration into solid tumors