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\begin{document}

\title{Editorial for Cancer Microenvironment and Pharmacological Interventions}



\author[1]{Mark  Williams}%
\author[2]{Monica  Guzman}%
\affil[1]{Glasgow Caledonian University}%
\affil[2]{Cornell University Joan and Sanford I Weill Medical College}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\textbf{Editorial on the themed issue:}

\emph{Cancer Microenvironment and Pharmacological Interventions}

\emph{Mark T.S. Williams and Monica L Guzman.}

The instrumental role that the cancer microenvironment plays in the
pathogenesis of cancer was highlighted over 130 years ago by Stephen
Paget, when he proposed the ``seed and soil'' hypothesis in 1889. He
suggested that cancer metastasis is dependent on the characteristics of
cancer cells the \emph{seed} , and also on the composition of the
supportive tissue microenvironment the \emph{soil} , in which the cancer
cells are able to successfully colonize. Despite advances in our
understanding of the tumour microenvironment (TME) and the bone marrow
microenvironment (BME), in the context of solid and haematological
malignancies respectively, for many years the complexity of the tumour
microenvironment has been somewhat overlooked. Most studies have been
cancer-cell focussed deciphering the genetic, molecular and biochemical
properties of cancer cells. These efforts have led to the generation of
cancer cell selective targeting treatments, including immunotherapies,
leading to some improvements in cancer patient outcomes. However, the
development of therapy resistance and relapse, which are in part driven
by the interaction of the cancer cells with their protective cancer
microenvironment, are major unmet clinical needs in the field of cancer
(Miari et al., 2021). Most FDA approved drugs solely target cancer
cells, and thus fail to modulate the cancer-promoting TME.

This themed issue aimed at collating articles critically discussing
cancer-supporting features of the tumour microenvironment in
haematological and solid malignancies, including the cellular (e.g.
mesenchymal stromal/stem cells) and non-cellular elements (e.g.
extracellular matrix; ECM components). The issue also captures
cutting-edge basic science (e.g. 3D \emph{in vitro} model systems), to
more accurately model and therapeutically target cancer cell-to-TME
interactions, with the intention of improving the likelihood of
identifying approaches that can improve the efficacy of existing
anti-cancer interventions, through to the development of novel
therapeutic interventions modulating the cancer-promoting TME.

Specifically, this themed issue there are six articles focussed on the
following:

Mesenchymal stromal/stem cells (MSCs) and cancer associated fibroblasts
(CAFs), along with tumour-associated macrophages (TAMs) (Cassetta and
Pollard, 2018), are one of the most prominent cell types present within
the TME, and have been the discussed in depth in this issue, as it is
included in three articles and thus, it represents the increasing amount
of studies investigating MSCs/CAFs as key drivers in: reprogramming the
microenvironment towards a cancer-permissive environment; cancer
development and progression; cancer therapy resistance, and serving as
therapeutic targets in cancer. Although research on MSCs/CAFs is highly
encouraging, it is predominantly still at the preclinical phase, with no
therapies targeting/modulating MSC/CAF function currently approved.
Therapeutic intervention at the level of MSCs/CAFs has been hindered
mainly due to the extensive diversity/heterogeneity of this cell
population (\textbf{Miari \& Williams} ). Interestingly, an
immunocytokine, Simlukafusp Alfa (FAP-IL2v), a monoclonal antibody (mAb)
targeting the CAF marker, fibroblast activation protein \selectlanguage{greek}α \selectlanguage{english}(FAP\selectlanguage{greek}α\selectlanguage{english}),
conjugated to an IL-2 variant (IL-2v), has been tested in a recently
completed Phase I clinical trial (\textbf{NCT02627274} ) (Waldhauer et
al., 2021). This therapy was tested in combination with the anti-HER2
and anti-EGFR mAbs Trastuzumab and Cetuximab respectively, for treating
breast cancer and head and neck cancer patients. This novel therapy
exploits the inherent tumour tropism of CAFs (\textbf{Borzone \&
Wheadon} ), coupled with the IL-2 variant retaining its propensity for
solely binding with high affinity to the IL-2 receptor signalling
subunits \selectlanguage{greek}β \selectlanguage{english}and \selectlanguage{greek}γ \selectlanguage{english}(IL-2R\selectlanguage{greek}βγ\selectlanguage{english}), immunstimulating (via T-cell expansion), and
subverting the immunosuppressive effects (via regulatory T cell
{[}Treg{]} mediated immune tolerance), associated with IL-2R\selectlanguage{greek}α
\selectlanguage{english}engagement/activation. Advantages of this therapy over traditional IL-2
cytokine therapies are two-fold. First, enhanced half-life of IL-2 and
efficacy to stimulate anti-tumour immune responses within the TME.
Second, circumventing severe adverse effects associated with
systemic/untargeted IL-2.

The fourth paper in the series by \textbf{Zou and colleagues}extensively
reviews the function, regulation, and distribution of the immune
checkpoint ligand programmed death-ligand 1 (PD-L1), as to better
understand these aspects, to aid development of strategies improving the
efficacy of PD-L1 immunotherapies/mAbs. There are 13 approved mAbs
targeting programmed cell death protein-1 (PD-1) or PD-L1, and these
have been revolutionary in treating patients with solid cancers.
However, the clinical efficacy of these immunotherapies has
disappointingly been less than predicted, resulting from several cancer
cell-inherent and TME-mediated resistance mechanisms.

One of the major immune (and potentially treatment) evasion strategies
is exogenous/exosomal PD-L1 (exoPD-L1), that is present on extracellular
vesicles (EVs) secreted by cancer cells. This mechanism is particularly
exemplified glioblastoma, in which glioblastoma cells release
PD-L1\textsuperscript{+} EVs, driving formation of immunosuppressive
monocytes capable of suppressing T-cell proliferation (Himes et al.,
2020). Importantly, this would potentially render PD-1/PD-L1 mAbs
clinically ineffective, via PD-L1\textsuperscript{+} EVs acting as a
decoy for PD-1/PD-L1 mAbs and preventing the targeting of cancer cells
and the surrounding immune microenvironment. ExoPD-L1 could serve as a
biomarker for PD-L1 immunotherapy response and has advantages over
conventional biopsy. Moreover, it is tempting to speculate that the
efficacy of anti-PD-L1 immunotherapy, could be enhanced by providing
cancer patients with a first low dose of anti-PD-L1 mAb, to bind to
decoy PD-L1\textsuperscript{+} EVs, with further doses used to target
PD-L1 present in cancer cells and immune cells within the TME.

Accurate modelling of cancer cell-to-TME interactions and overcoming TME
-driven therapy resistance in haematological and solid cancers, remain
as outstanding needs in the cancer field. Current \emph{in vitro}
and\emph{in vivo} models for investigating cancer cell-to-TME
interactions, predominantly rely on the use of 2D \emph{in vitro}
co-culture model systems and xenograft murine models. However, there are
caveats associated with these model systems. 2D model systems
overestimate therapeutic efficacy (Dainiak et al., 2008), failing to
translate into clinical efficacy. Furthermore, xenograft mouse models
lack a functional immune system, with findings generated from these
models not directly applicable to humans, as human cancer cell-human TME
interactions differ from human cancer cell-murine TME interactions at
the cellular and molecular level (\textbf{Martinez \& Guzman} ).
Three-dimensional model systems, incorporating TME-resident cells (e.g.
X,Y,Z) and ECM components hold much promise (\textbf{Nyamondo \&
Wheadon} ) as they more accurately reflect TME features, such as hypoxia
and reactive oxygen species, not present in most 2D models. Furthermore,
3D models mirror the well-established therapy resistant effects
previously reported for the TME. \textbf{Ogana et al} discussed
targeting integrins to overcome TME-elicited drug resistance in acute
myeloid leukaemia (AML). Although no integrin-targeted treatments have
been approved to date, this represents a potentially effective
therapeutic approach not just in AML, but also for other blood cancers
and solid cancers, to circumvent cell adhesion-mediated drug resistance
(CAM-DR).

To summarise, conclusions of the articles in this issue provide novel
insights into how alterations in cellular and non-cellular components of
the microenvironment drive cancer development and progression, and
mediate therapy resistance/failure, promoting relapse and sub-optimal
clinical outcomes in cancer patients. Despite the extensive evidence on
these highly important issues, these articles show that there are
several outstanding features to be determined in the fascinating area of
cancer microenvironment and pharmacological intervention. After reading
this issue, aspects such as, modelling and targeting complex cancer
cell-to-TME interactions to improve the efficacy of existing and new
therapies, will become more apparent to the reader. This will reinforce
the concept that studies identifying and targeting cancer-cell-inherent
and cancer microenvironment driven mechanisms of resistance, are still
crucially needed to enhance survival and quality of life in cancer
patients.

CASSETTA, L. \& POLLARD, J. W. 2018. Targeting macrophages: therapeutic
approaches in cancer. \emph{Nature Reviews Drug Discovery,}
17\textbf{,}887-904.

DAINIAK, M. B., SAVINA, I. N., MUSOLINO, I., KUMAR, A., MATTIASSON, B.
\& GALAEV, I. Y. 2008. Biomimetic macroporous hydrogel scaffolds in a
high-throughput screening format for cell-based assays. \emph{Biotechnol
Prog,} 24\textbf{,} 1373-83.

HIMES, B. T., PETERSON, T. E., DE MOOIJ, T., GARCIA, L. M. C., JUNG, M.
Y., UHM, S., YAN, D., TYSON, J., JIN-LEE, H. J., PARNEY, D., ABUKHADRA,
Y., GUSTAFSON, M. P., DIETZ, A. B., JOHNSON, A. J., DONG, H., MAUS, R.
L., MARKOVIC, S., LUCIEN, F. \& PARNEY, I. F. 2020. The role of
extracellular vesicles and PD-L1 in glioblastoma-mediated
immunosuppressive monocyte induction. \emph{Neuro Oncol,}
22\textbf{,}967-978.

MIARI, K. E., GUZMAN, M. L., WHEADON, H. \& WILLIAMS, M. T. S. 2021.
Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy
Resistance and Patient Outcomes. \emph{Frontiers in Cell and
Developmental Biology,} 9.

WALDHAUER, I., GONZALEZ-NICOLINI, V., FREIMOSER-GRUNDSCHOBER, A., NAYAK,
T. K., FAHRNI, L., HOSSE, R. J., GERRITS, D., GEVEN, E. J. W., SAM, J.,
LANG, S., BOMMER, E., STEINHART, V., HUSAR, E., COLOMBETTI, S., VAN
PUIJENBROEK, E., NEUBAUER, M., CLINE, J. M., GARG, P. K., DUGAN, G.,
CAVALLO, F., ACUNA, G., CHARO, J., TEICHGR\selectlanguage{ngerman}ÄBER, V., EVERS, S., BOERMAN,
O. C., BACAC, M., MOESSNER, E., UMAÑA, P. \& KLEIN, C. 2021. Simlukafusp
alfa (FAP-IL2v) immunocytokine is a versatile combination partner for
cancer immunotherapy. \emph{MAbs,} 13\textbf{,} 1913791.

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