Bio

Gita Abhiraman is a resident physician in Internal Medicine at Stanford in the Translational Investigator Program. She completed her MD and PhD at Stanford in the Medical Scientist Training Program. Her PhD in Immunology was advised by Dr. Chris Garcia, in which she studied cytokine signaling, immune receptor structure, and protein engineering. Her major first author-works include solving the structure of the interleukin-21 signaling receptor complex. She also developed a cytokine "adapter" switch molecule with applications in cancer and autoimmune disease. Gita has been involved in several projects to engineer cytokines, including IL-21, IL-12, and IL-10, for diverse therapeutic applications. Prior to her graduate training, Gita completed a bachelor's degree in Physics with a focus in Biophysics at Harvard University. She previously conducted research in the lab of Dr. Stephanie Dougan at the Dana-Farber Cancer Institute.

Honors & Awards

  • Hertz Fellow, The Fannie and John Hertz Foundation (2021)

Professional Education

  • MD, Stanford University School of Medicine
  • PhD, Stanford University School of Medicine, Immunology
  • BA, Harvard University, Physics

Additional Info

All Publications

  • Design of a potent interleukin-21 mimic for cancer immunotherapy. Science immunology Chun, J. H., Lim, B. S., Roy, S., Walsh, M. J., Abhiraman, G. C., Zhangxu, K., Atajanova, T., Revach, O. Y., Clark, E. C., Li, P., Palin, C. A., Khanna, A., Tower, S., Kureshi, R., Hoffman, M. T., Sharova, T., Lawless, A., Cohen, S., Boland, G. M., Nguyen, T., Peprah, F., Tello, J. G., Liu, S. Y., Kim, C. J., Shin, H., Quijano-Rubio, A., Jude, K. M., Gerben, S., Murray, A., Heine, P., DeWitt, M., Ulge, U. Y., Carter, L., King, N. P., Silva, D. A., Kueh, H. Y., Kalia, V., Sarkar, S., Jenkins, R. W., Garcia, K. C., Leonard, W. J., Dougan, M., Dougan, S. K., Baker, D. 2025; 10 (111): eadx1582

    Abstract

    Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a range of affinities for tumor antigens while suppressing regulatory T cells. Computational protein design has enabled the precise tailoring of proteins to meet specific needs. Here, we report a de novo designed IL-21 mimic, 21h10, with high stability and signaling potency in humans and mice. In murine and ex vivo human organotypic tumor models, 21h10 showed robust antitumor activity, with more prolonged signaling and stronger antitumor activity than native IL-21. 21h10 induced pancreatitis that could be mitigated by TNF blockade without compromising antitumor efficacy. Although antidrug antibodies to 21h10 formed, they were not neutralizing. 21h10 induced highly cytotoxic T cells with a range of affinities, robustly expanding intratumoral low-affinity cytotoxic T cells and driving high expression of IFN-γ and granzyme B compared with native IL-21, while increasing the frequency of IFN-γ+ T helper 1 cells and reducing regulatory T cells. The full human-mouse cross-reactivity, high stability and potency, and low-affinity antitumor responses support the translational potential of 21h10.

    View details for DOI 10.1126/sciimmunol.adx1582

    View details for PubMedID 41004565

  • Spontaneous and experimental models of lymph node metastasis. Nature protocols Breuer, C. B., Xiong, Z., Wang, A., Rodriguez, G. E., Abhiraman, G. C., Garcia, K. C., Reticker-Flynn, N. E. 2025

    Abstract

    Lymph node (LN) metastasis is a conserved feature across most solid organ malignancies and portends worse prognoses. Functionally, LN metastases induce systemic tumor-specific immune tolerance and may serve as a reservoir for distant metastases. Nonetheless, there are relatively few preclinical models for interrogating the biology of LN metastasis and its systemic effects at various stages of metastatic progression. We describe a method for modeling LN metastasis of melanoma tumors in mice that enables assessment of tumor and immune cell phenotypes and the functional roles of nodal involvement on distant metastasis. Our model comprises a family of transplantable syngeneic melanoma tumor cell lines evolved to exhibit enhanced LN metastatic potential, which can be used to probe cancer-immune interactions and test new therapeutics. We present both (i) a spontaneous LN metastasis model involving primary tumor implantation and assessment of LN colonization 21-28 d later and (ii) an experimental metastasis model involving implantation of primary tumors followed by direct intra-LN injections of tumor cells. Both models can be extended to assess the impact of LN metastasis on the development of distant metastases through asynchronous intravenous injections of tumors. Finally, we discuss experimental design considerations including when to use spontaneous or experimental models and troubleshooting consistent LN metastasis, making this model accessible for researchers with basic mouse survival-surgery skills. We highlight how LN metastasis models can be used to profile metastatic immune reprogramming, measure the impact of nodal metastases on distant metastases and assess novel anti-metastatic therapeutics.

    View details for DOI 10.1038/s41596-025-01200-5

    View details for PubMedID 40804176

    View details for PubMedCentralID 10511214

  • Redirecting immune signaling with cytokine adaptors. Nature communications Abhiraman, G. C., Householder, K. D., Rodriguez, G. E., Glassman, C. R., Saxton, R. A., Breuer, C. B., Wilson, S. C., Su, L., Yen, M., Hsu, C., Pillarisetty, V. G., Reticker-Flynn, N. E., Garcia, K. C. 2025; 16 (1): 2432

    Abstract

    Cytokines are signaling molecules that coordinate complex immune processes and are frequently dysregulated in disease. While cytokine blockade has become a common therapeutic modality, cytokine agonism has had limited utility due to the widespread expression of cytokine receptors with pleiotropic effects. To overcome this limitation, we devise an approach to engineer molecular switches, termed cytokine adaptors, that transform one cytokine signal into an alternative signal with a different functional output. Endogenous cytokines act to nucleate the adaptors, converting the cytokine-adaptor complex into a surrogate agonist for a different cytokine pathway. In this way, cytokine adaptors, which have no intrinsic agonist activity, can function as conditional, context-dependent agonists. We develop cytokine adaptors that convert IL-10 or TGF-β into IL-2 receptor agonists to reverse T cell suppression. We also convert the pro-inflammatory cytokines IL-23 or IL-17 into immunosuppressive IL-10 receptor agonists. Thus, we show that cytokine adaptors can convert immunosuppressive cytokines into immunostimulatory cytokines, or vice versa. Unlike other methods of immune conversion that require cell engineering, cytokine adaptors are soluble molecules that leverage endogenous cues from the microenvironment to drive context-specific signaling.

    View details for DOI 10.1038/s41467-025-57681-1

    View details for PubMedID 40069219

    View details for PubMedCentralID 4804829

  • Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint. Cell reports Mardjuki, R., Wang, S., Carozza, J., Zirak, B., Subramanyam, V., Abhiraman, G., Lyu, X., Goodarzi, H., Li, L. 2024: 114209

    Abstract

    2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for cancer immunotherapy.

    View details for DOI 10.1016/j.celrep.2024.114209

    View details for PubMedID 38749434

  • Overcoming lung cancer immunotherapy resistance by combining non-toxic variants of IL-12 and IL-2. JCI insight Horton, B. L., D'Souza, A. D., Zagorulya, M., McCreery, C. V., Abhiraman, G. C., Picton, L. K., Sheen, A., Agarwal, Y., Momin, N., Wittrup, K. D., White, F. M., Garcia, K. C., Spranger, S. 2023

    Abstract

    Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.

    View details for DOI 10.1172/jci.insight.172728

    View details for PubMedID 37669107

  • A structural blueprint for interleukin-21 signal modulation. Cell reports Abhiraman, G. C., Bruun, T. U., Caveney, N. A., Su, L. L., Saxton, R. A., Yin, Q., Tang, S., Davis, M. M., Jude, K. M., Garcia, K. C. 2023; 42 (6): 112657

    Abstract

    Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and association with autoimmune disease. To better understand the structural basis of IL-21 signaling, we determine the structure of the IL-21-IL-21R-γc ternary signaling complex by X-ray crystallography and a structure of a dimer of trimeric complexes using cryo-electron microscopy. Guided by the structure, we design analogs of IL-21 by introducing substitutions to the IL-21-γc interface. These IL-21 analogs act as partial agonists that modulate downstream activation of pS6, pSTAT3, and pSTAT1. These analogs exhibit differential activity on T and B cell subsets and modulate antibody production in human tonsil organoids. These results clarify the structural basis of IL-21 signaling and offer a potential strategy for tunable manipulation of humoral immunity.

    View details for DOI 10.1016/j.celrep.2023.112657

    View details for PubMedID 37339051

  • Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science (New York, N.Y.) Saxton, R. A., Tsutsumi, N., Su, L. L., Abhiraman, G. C., Mohan, K., Henneberg, L. T., Aduri, N. G., Gati, C., Garcia, K. C. 2021; 371 (6535)

    Abstract

    Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Ralpha form a composite surface to engage the shared signaling receptor IL-10Rbeta, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rbeta binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.

    View details for DOI 10.1126/science.abc8433

    View details for PubMedID 33737461

  • Generation of Ca2+-independent sortase A mutants with enhanced activity for protein and cell surface labeling PLOS ONE Jeong, H., Abhiraman, G. C., Story, C. M., Ingram, J. R., Dougan, S. K. 2017; 12 (12): e0189068

    Abstract

    Sortase A, a calcium-dependent transpeptidase derived from Staphylococcus aureus, is used in a broad range of applications, such as the conjugation of fluorescent dyes and other moieties to proteins or to the surface of eukaryotic cells. In vivo and cell-based applications of sortase have been somewhat limited by the large range of calcium concentrations, as well as by the often transient nature of protein-protein interactions in living systems. In order to use sortase A for cell labeling applications, we generated a new sortase A variant by combining multiple mutations to yield an enzyme that was both calcium-independent and highly active. This variant has enhanced activity for both N- and C-terminal labeling, as well as for cell surface modification under physiological conditions.

    View details for DOI 10.1371/journal.pone.0189068

    View details for Web of Science ID 000417033200027

    View details for PubMedID 29200433

    View details for PubMedCentralID PMC5714338

https://orcid.org/0000-0002-0546-4133