GEN-IsoPlexis_RT_Nov22_Single-CellAdvances - 9

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different polarization in a different situation, thereby creating
challenges for data discovery and interpretation. This is where
proteomic cytokine responses are necessary to understand the
way immune cells are programmed or exhibit plasticity. Those
who do classical analysis with how cytokines are produced will
tell you that almost any inflammatory insult means that the
lymphocytes or innate immune cells prepare themselves with
certain kinds of mRNA. Whether they will produce proteins
coded by these mRNA and ultimately secrete them is really
defined by where they are embedded in the ecosystem, what
they are responding to, and whether there is a suitable stimulus
or not. This is oftentimes the difference between, for example,
defining a responder or nonresponder cancer patient.
So it's no surprise that when these new transcriptomically
defined immune subsets are ready for translation in clinical
data, many of them don't work out because their stability with
respect to a therapy-responsive functional ecosystem wasn't
established. Thus, a proteomics-based cytokines response has
a higher chance of giving you more reliable biomarkers of a
functionally relevant ecosystem.
On the downside, the accessibility, the costs, and the work
involved in processing and freezing (if possible, otherwise live
processing) the samples in a certain way is a lot of work for
some clinical units, who may not have enough resources to
achieve this. I think sometimes, unfortunately, the knowledge
gap is frustratingly practical, i.e., costs and personnel. Thus,
increasing cost-effectiveness of such technologies is also
necessary to increase their usability.
Luca Gattinoni:
For cancer, there are already papers showing that the
ability of a CAR-T cell product to release multiple types of
cytokines at the single-cell level enables the segregation of
responders versus nonresponders. This is not achievable by
other assays such as bulk multiplexed secretomic assays.
Single-cell functional secretomics can also be used for
immunomonitoring CAR-T cell products ex vivo. This is
done more rarely, but it can provide important information
on how CAR-T cell functionality evolves after transfer into
patients. For instance, it could reveal how long CAR-T cells
can maintain polyfunctionality in vivo or if they become
more or less polyfunctional, or if they modify the type
of cytokines released overtime. Together with single-cell
clonotype analyses, it could provide us with a better picture
of the differentiation trajectories that CAR-T or TCR-T cells
experience after transfer into patients.
For respiratory diseases, I think about respiratory
infections, such as COVID-19. Having viral-specific cells
that are capable of releasing multiple cytokines at the same
time is likely beneficial. To this end, single-cell functional
secretomics could be used as a readout in the development
of vaccines. Currently, the potency of a vaccine is mostly
measured by evaluating its ability to induce an antibody
response, even if we know that the cellular memory response
is also important. Developing strategies capable of inducing
memory cells with heightened polyfunctional capacities
could potentially lead to more effective vaccines.
Peggy Sotiropoulou:
By having access to more detailed and precise information
at each stage of the development process, we can be smarter
and more efficient in creating therapies that ultimately better
serve the needs of patients. In cancer, more intelligent data are
required across all stages of development-starting from the
preclinical stage, to the analysis of the infusion product, and
through the clinical studies while patient responses are being
monitored. Understanding the proteomic cytokine response
will increase our ability to understand immune biology and
interactions with the tumor. This knowledge will allow us to
reengineer the body's natural biology to achieve more efficient
immune responses and better clinical outcomes.
GEN: How does understanding the function
of different cell types evolved in the immune
response help accelerate the development of
novel therapies?
Luca Gattinoni:
Understanding how diverse T cell subsets are generated
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