Santosh Vardhana
@santoshvardhana.bsky.social
Researching immunology, metabolism, and cancer, and caring for patients with lymphoma at MSKCC (www.vardhanalab.com). Opinions are my own.
I know she will continue to do great things as a post-doctoral fellow in Jeff Rathmell's lab, but we will miss her tremendously (and not just for her willingness to teach the lab TikTok dances). /end
July 16, 2026 at 9:56 PM
I know she will continue to do great things as a post-doctoral fellow in Jeff Rathmell's lab, but we will miss her tremendously (and not just for her willingness to teach the lab TikTok dances). /end
Incredibly proud of @tanmanamitra.bsky.social, who took a chance on me when my lab was so young that she sat at my post-doc desk in Craig Thompson’s lab while I frantically ran across the street to try to unpack boxes in the new lab.
Moving Day Cat in a Box
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July 16, 2026 at 9:56 PM
Incredibly proud of @tanmanamitra.bsky.social, who took a chance on me when my lab was so young that she sat at my post-doc desk in Craig Thompson’s lab while I frantically ran across the street to try to unpack boxes in the new lab.
These results have significant clinical implications, as they suggest that MEK inhibition may preserve immunotherapy responsiveness under conditions in which T cells face a high bioenergetic load (either a limited neoantigen burden or relatively few progenitor-like Texh cells.
July 16, 2026 at 9:56 PM
These results have significant clinical implications, as they suggest that MEK inhibition may preserve immunotherapy responsiveness under conditions in which T cells face a high bioenergetic load (either a limited neoantigen burden or relatively few progenitor-like Texh cells.
In response to this increased demand, T cells increase nutrient uptake, which over time leads to ROS accumulation and terminal T cell exhaustion. (We know how: stay tuned)
Star Wars Yoda: Patience You Must Learn
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July 16, 2026 at 9:56 PM
In response to this increased demand, T cells increase nutrient uptake, which over time leads to ROS accumulation and terminal T cell exhaustion. (We know how: stay tuned)
Together, these results indicate that TCR-dependent MEK activation sets ATP demand in exhausted T cells by regulating the transcription and translation of terminal effector and exhaustion genes.
July 16, 2026 at 9:56 PM
Together, these results indicate that TCR-dependent MEK activation sets ATP demand in exhausted T cells by regulating the transcription and translation of terminal effector and exhaustion genes.
Moreover, sequencing of nascently transcribed RNA revealed that chronic MEK activation drives preferential transcription of genes expressed by terminally exhausted T cells, including immune checkpoints but also genes required for cytotoxic granule assembly and function.
Avengers Assemble: Ready for Battle
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July 16, 2026 at 9:56 PM
Moreover, sequencing of nascently transcribed RNA revealed that chronic MEK activation drives preferential transcription of genes expressed by terminally exhausted T cells, including immune checkpoints but also genes required for cytotoxic granule assembly and function.
Tanmana confirmed that persistent antigen encounter, both in vitro and in vivo, was sufficient to increase nascent transcription rates in a MEK dependent fashion.
July 16, 2026 at 9:56 PM
Tanmana confirmed that persistent antigen encounter, both in vitro and in vivo, was sufficient to increase nascent transcription rates in a MEK dependent fashion.
Tanmana went one step further by asking how MEK regulates protein synthesis. In embryonic stem cells, MEK regulates exit from pluripotency in part by phosphorylating and releasing RNA polymerase II from a ‘paused’ state at promoters of lineage specific genes.
July 16, 2026 at 9:56 PM
Tanmana went one step further by asking how MEK regulates protein synthesis. In embryonic stem cells, MEK regulates exit from pluripotency in part by phosphorylating and releasing RNA polymerase II from a ‘paused’ state at promoters of lineage specific genes.
Indeed, acute cycloheximide treatment confirmed that nearly all of chronic TCR-driven bioenergetic demand is due to an increased demand for protein synthesis, and this is fully reversed by MEK inhibition.
July 16, 2026 at 9:56 PM
Indeed, acute cycloheximide treatment confirmed that nearly all of chronic TCR-driven bioenergetic demand is due to an increased demand for protein synthesis, and this is fully reversed by MEK inhibition.
Using click chemistry (hat tip to @carolynbertozzi.bskyverified.social), Tanmana demonstrated that MEK inhibition attenuated the rate of protein translation, indicating that MEK sets the bioenergetic demand of exhausted T cells by altering the balance of ATP synthesis versus NAD+ regeneration.
July 16, 2026 at 9:56 PM
Using click chemistry (hat tip to @carolynbertozzi.bskyverified.social), Tanmana demonstrated that MEK inhibition attenuated the rate of protein translation, indicating that MEK sets the bioenergetic demand of exhausted T cells by altering the balance of ATP synthesis versus NAD+ regeneration.
This is consistent with pioneering work from Martin Brand showing that in proliferating rat thymocytes, protein synthesis is a substantial (or even dominant) source of ATP demand.
July 16, 2026 at 9:56 PM
This is consistent with pioneering work from Martin Brand showing that in proliferating rat thymocytes, protein synthesis is a substantial (or even dominant) source of ATP demand.
Tanmana next asked how MEK regulates bioenergetic demand in exhausted T cells. MEK inhibition reduced expression of genes related to protein synthesis, leading her to hypothesize that MEK regulates bioenergetic demand in Texh at the level of protein synthesis.
July 16, 2026 at 9:56 PM
Tanmana next asked how MEK regulates bioenergetic demand in exhausted T cells. MEK inhibition reduced expression of genes related to protein synthesis, leading her to hypothesize that MEK regulates bioenergetic demand in Texh at the level of protein synthesis.
These findings paralleled those of several groups which have shown a benefit to MEK inhibition for cancer immunotherapy.
July 16, 2026 at 9:56 PM
These findings paralleled those of several groups which have shown a benefit to MEK inhibition for cancer immunotherapy.
Tanmana identified MEK as the primary driver of nutrient uptake, mitochondrial ATP production, and ROS accumulation; consequently, targeting MEK reduced nutrient uptake, rebalanced NADH/NAD+ ratios, and increased T cell proliferation, and reduced terminal T cell exhaustion.
July 16, 2026 at 9:56 PM
Tanmana identified MEK as the primary driver of nutrient uptake, mitochondrial ATP production, and ROS accumulation; consequently, targeting MEK reduced nutrient uptake, rebalanced NADH/NAD+ ratios, and increased T cell proliferation, and reduced terminal T cell exhaustion.
This explained both why chronic TCR stimulation immediately decreased T cell proliferation, as well as the mechanism by which chronic TCR stimulation causes ROS accumulation (via reductive stress).
July 16, 2026 at 9:56 PM
This explained both why chronic TCR stimulation immediately decreased T cell proliferation, as well as the mechanism by which chronic TCR stimulation causes ROS accumulation (via reductive stress).
What Tanmana discovered was that this paradigm is broken during chronic TCR stimulation, which drives mitochondrial NADH accumulation to support ATP synthesis at the expense of NAD+ regeneration.
July 16, 2026 at 9:56 PM
What Tanmana discovered was that this paradigm is broken during chronic TCR stimulation, which drives mitochondrial NADH accumulation to support ATP synthesis at the expense of NAD+ regeneration.
This was confusing to us, as @mvhlab.bsky.social recently showed that the primary driver for reducing pyruvate to lactate rather than fully oxidizing it in the TCA cycle was a demand for NAD that outweighed the demand for ATP in proliferating cells, including T cells.
July 16, 2026 at 9:56 PM
This was confusing to us, as @mvhlab.bsky.social recently showed that the primary driver for reducing pyruvate to lactate rather than fully oxidizing it in the TCA cycle was a demand for NAD that outweighed the demand for ATP in proliferating cells, including T cells.
She further showed that this rate of NADH generation was due primarily to increased rates of glucose uptake and entry of glucose-derived carbons into the TCA cycle.
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July 16, 2026 at 9:56 PM
She further showed that this rate of NADH generation was due primarily to increased rates of glucose uptake and entry of glucose-derived carbons into the TCA cycle.
Tanmana found that chronic TCR stimulation immediately elevated the NADH/NAD+ ratio despite also increasing oxygen consumption compared with conventionally activated cells, favoring excess NADH generation over ETC dysfunction as the primary source of ROS in these cells.
David Rose: It's Too Much!
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July 16, 2026 at 9:56 PM
Tanmana found that chronic TCR stimulation immediately elevated the NADH/NAD+ ratio despite also increasing oxygen consumption compared with conventionally activated cells, favoring excess NADH generation over ETC dysfunction as the primary source of ROS in these cells.
The way we saw it, ADP-coupled oxidative phosphorylation could be perturbed only if there were 1) a lack of oxygen, 2) impaired electron transport, or 3) delivery of electrons at a rate that exceeded the maximal rate of electron transport.
July 16, 2026 at 9:56 PM
The way we saw it, ADP-coupled oxidative phosphorylation could be perturbed only if there were 1) a lack of oxygen, 2) impaired electron transport, or 3) delivery of electrons at a rate that exceeded the maximal rate of electron transport.
We tried to think about this in as simple a way as possible (which we frequently like to do in the lab).
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July 16, 2026 at 9:56 PM
We tried to think about this in as simple a way as possible (which we frequently like to do in the lab).
As I started my own lab, I had two major questions about this finding. Our prior paper had established that chronic TCR stimulation was sufficient to drive mitochondrial dysfunction. But how? What about chronic TCR stimulation makes T cells accumulate ROS?
July 16, 2026 at 9:56 PM
As I started my own lab, I had two major questions about this finding. Our prior paper had established that chronic TCR stimulation was sufficient to drive mitochondrial dysfunction. But how? What about chronic TCR stimulation makes T cells accumulate ROS?
Our laboratory’s contribution to this this was the identification that reactive oxygen species (ROS)-driven loss of mitochondrial ATP production was sufficient to block chronic TCR-driven loss of proliferation and drive terminal differentiation: www.nature.com/articles/s41...
Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen - Nature Immunology
Thompson and colleagues show that repetitive antigenic stimulation within the tumor environment triggers mitochondrial dysfunction by inhibiting oxidative phosphorylation, which leads to T cell exhaus...
www.nature.com
July 16, 2026 at 9:56 PM
Our laboratory’s contribution to this this was the identification that reactive oxygen species (ROS)-driven loss of mitochondrial ATP production was sufficient to block chronic TCR-driven loss of proliferation and drive terminal differentiation: www.nature.com/articles/s41...
It’s increasingly appreciated that mitochondrial dysfunction is a hallmark of terminal T cell exhaustion (shout out to Rathmell, @delgoffelab.bsky.social, Ping-Chih Ho labs.
July 16, 2026 at 9:56 PM
It’s increasingly appreciated that mitochondrial dysfunction is a hallmark of terminal T cell exhaustion (shout out to Rathmell, @delgoffelab.bsky.social, Ping-Chih Ho labs.