Science - USA (2022-01-07)

on the type of chemotherapy used or on the
concomitant treatment with steroids.
One important factor to consider is that al-
though inducing or augmenting TLS function
may improve tumor control, such interventions
may at the same time boost autoreactive T and
B cell responses at other tissue sites. Autoim-
mune reactions are observed as the main
type of toxicity after ICB, and these so-called
immune-related adverse events resemble the
inflammatory processes that are often found
in autoimmune diseases, including arthritis,
myositis, thyroiditis, vasculitis, and colitis ( 147 ).
Considering that TLSs have been found to
support local inflammatory processes in many
autoimmune diseases, it is conceivable that
approaches that boost TLS numbers or TLS
functionality could also increase ICB-induced
autoimmune toxicity. Although, at present, few
data exist on the role of TLSs in immune-
related adverse events, an association between
TLS formation and autoimmune myopathy
upon PD-1 blockade has been reported. Spe-
cifically, biopsies from patients presenting
with myalgia and muscle weakness after anti–
PD-1 treatment revealed CD8+T cell–driven
muscle tissue destruction that was associated
with the formation of TLS-like structures ex-
pressing PNAd and CCL21 ( 148 ). Hence, induc-
tion or boosting of TLS function may promote
not only antitumor responses but also the ex-
pansion of autoreactive T and B cells, and the
risk-benefit ratio of such approaches therefore
needs to be carefully evaluated.

Concluding remarks

Recent studies describing the prognostic and

predictive value of TLSs in cancer have fueled

interest in these structures as potential media-

tors of antitumor immunity. Based on available

evidence, it is plausible that TLSs contribute

to the strength of tumor-specific immune

responses. However, whether this primarily

involves the boosting of T cell responses gen-

erated in SLOs or the development of new

T and B cell reactivities remains a key un-

answered question. Similarly, the presence

of TLSs at the tumor site offers a clear pos-

sibility for the generation of qualitatively dis-

tinct immune responses through the effects of

local tissue factors. However, direct evidence

for a distinct nature of immune responses that

are formed or boosted in TLSs is presently

lacking. Although TLSs have been described

in numerous cancer types and their prognostic

value is beyond doubt, the usage of consistent

markers to define and characterize TLSs should

form an area of future attention to maximize

the value of these structures as potential bio-

markers. Related to this, a more comprehen-

sive characterization of TLSs would likely help

provide a definition of a spectrum of“TLS

states,”based on aspects such as cellular com-

position, location, maturation, and function

(Fig. 3). Much like the definition of T cell

states has helped the field to better under-

stand their role in cancer control, the molec-

ular definition of TLS states could improve

their value as prognostic and predictive mark-

ers. Finally, a more detailed understanding of

TLS function and their potential role in auto-

immune toxicity will be helpful to appreciate

their value as therapeutic targets.

REFERENCESANDNOTES

1. J. Galonet al., Type, density, and location of immune cells
   within human colorectal tumors predict clinical outcome.
   Science 313 , 1960–1964 (2006). doi:10.1126/
   science.1129139; pmid: 17008531


2. F. Pagèset al., International validation of the consensus
   Immunoscore for the classification of colon cancer:
   A prognostic and accuracy study.Lancet 391 , 2128– 2139
   (2018). doi:10.1016/S0140-6736(18)30789-X;
   pmid: 29754777


3. W. H. Fridman, F. Pagès, C. Sautès-Fridman, J. Galon,
   The immune contexture in human tumours: Impact on clinical
   outcome.Nat. Rev. Cancer 12 , 298–306 (2012). doi:10.1038/
   nrc3245; pmid: 22419253


4. S. A. Rosenberg, N. P. Restifo, Adoptive cell transfer as
   personalized immunotherapy for human cancer.Science 348 ,
   62 – 68 (2015). doi:10.1126/science.aaa4967; pmid: 25838374


5. D. M. Pardoll, The blockade of immune checkpoints in cancer
   immunotherapy.Nat. Rev. Cancer 12 , 252–264 (2012).
   doi:10.1038/nrc3239; pmid: 22437870


6. F. S. Hodiet al., Improved survival with ipilimumab in patients
   with metastatic melanoma.N. Engl. J. Med. 363 , 711– 723
   (2010). doi:10.1056/NEJMoa1003466; pmid: 20525992


7. S. L. Topalian, C. G. Drake, D. M. Pardoll, Targeting the
   PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity.
   Curr. Opin. Immunol. 24 , 207–212 (2012). doi:10.1016/
   j.coi.2011.12.009; pmid: 22236695


8. R. S. Herbstet al., Predictive correlates of response to the
   anti-PD-L1 antibody MPDL3280A in cancer patients.
   Nature 515 , 563–567 (2014). doi:10.1038/nature14011;
   pmid: 25428504


9. P. C. Tumehet al., PD-1 blockade induces responses by
   inhibiting adaptive immune resistance.Nature 515 , 568– 571
   (2014). doi:10.1038/nature13954; pmid: 25428505


10. F. Azimiet al., Tumor-infiltrating lymphocyte grade is an
    independent predictor of sentinel lymph node status and
    survival in patients with cutaneous melanoma.J. Clin. Oncol.

Schumacher and Thommen,Science 375 , eabf9419 (2022) 7 January 2022 7 of 10

B cells

(naïve, mature, memory,

plasma cells)

T cells

(naïve, CTL, dysfunctional,

TH1, TH2, TH17, TFH, Treg)

DCs

(DC-LAMP+, mature,

myeloid suppressors)

FDCs

(+local

substitutes)

FRCs

(+local

substitutes)

HEVs

Cellular composition

Maturation

Localization

Molecular characteristics

Lymphoid

aggregate

Primary

follicle

peritumoral

intratumoral

TCR

BCR/Ig clonality

clonality

Hypermutation/AID expression

T cell zone

Germinal center /B cell zone Cytokines

Chemokines

stromal

Secondary

follicle

Fig. 3. Defining TLS states.A comprehensive molecular definition of TLS states using a consistent set of parameters should improve their value as prognostic and
predictive biomarkers. Aspects that will provide more insight into the existence of TLS states include their cellular composition, location, and maturation; the
molecular characteristics of their cytokine and chemokine milieu; and their B cell receptor (BCR) and T cell receptor (TCR) repertoires. AID, activation-induced
cytidine deaminase; CTL, cytotoxic T lymphocyte; Ig, immunoglobulin.

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